Annulated 2-amino-3-cyano thiophenes and derivatives for the treatment of cancer

ABSTRACT

The present invention encompasses compounds of formula (I), wherein R 1a , R 1b , R 2a , R 2b , Z, R 3 , R 5 , A, U, V, W, L and E have the meanings given in the claims and specification, their use as inhibitors of mutant Ras family proteins, pharmaceutical compositions and preparations containing such compounds and their use as medicaments/medical uses, especially as agents for treatment and/or prevention of oncological diseases.

FIELD OF THE INVENTION

The present invention relates to annulated 2-amino-3-cyano thiophenesand derivatives of formula (I)

wherein R^(1a), R^(1b), R^(2a), R^(2b), Z, R³, R⁵, A, U, V, W, L and Ehave the meanings given in the claims and specification, their use asinhibitors of mutant Ras family proteins, pharmaceutical compositionsand preparations containing such compounds and their use asmedicaments/medical uses, especially as agents for treatment and/orprevention of oncological diseases, e.g. cancer.

BACKGROUND OF THE INVENTION

Ras family proteins including KRAS (V-Ki-ras2 Kirsten rat sarcoma viraloncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog) andHRAS (Harvey murine sarcoma virus oncogene) and any mutants thereof aresmall GTPases that exist in cells in either GTP-bound or GDP-boundstates (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3):253-8;Nimnual et al., Sci. STKE., 2002, 2002(145):pe36). The Ras familyproteins have a weak intrinsic GTPase activity and slow nucleotideexchange rates (Hunter et al., Mol. Cancer Res., 2015, 13(9):1325-35).Binding of GTPase activating proteins (GAPs) such as NF1 increases theGTPase activity of Ras family proteins. The binding of guaninenucleotide exchange factors (GEFs) such as SOS1 (Son of Sevenless 1)promote release GDP from Ras family proteins, enabling GTP binding(Chardin et al., Science, 1993, 260(5112):1338-43). When in theGTP-bound state, Ras family proteins are active and engage effectorproteins including C-RAF and phosphoinositide 3-kinase (PI3K) to promotethe RAF/mitogen or extracellular signal-regulated kinases (MEK/ERK)pathway, PI3K/AKT/mammalian target of rapamycin (mTOR) pathway andRaIGDS (RaI guanine nucleotide dissociation stimulator) pathway(McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3):253-8;Rodriguez-Viciana et al., Cancer Cell. 2005, 7(3):205-6). These pathwaysaffect diverse cellular processes such as proliferation, survival,metabolism, motility, angiogenesis, immunity and growth (Young et al.,Adv. Cancer Res., 2009, 102:1-17; Rodriguez-Viciana et al., Cancer Cell.2005, 7(3):205-6).

Cancer-associated mutations in Ras family proteins suppress theirintrinsic and GAP-induced GTPase activity leading to an increasedpopulation of GTP-bound/active mutant Ras family proteins (McCormick etal., Expert Opin. Ther. Targets., 2015, 19(4):451-4; Hunter et al., Mol.Cancer Res., 2015, 13(9):1325-35). This in turn leads to persistentactivation of effector pathways (e.g. RAF/MEK/ERK, PI3K/AKT/mTOR, RaIGDSpathways) downstream of mutant Ras family proteins. KRAS mutations (e.g.amino acids G12, G13, Q61, A146) are found in a variety of human cancersincluding lung cancer, colorectal cancer and pancreatic cancer (Cox etal., Nat. Rev. Drug Discov., 2014, 13(11):828-51). Mutations in HRAS(e.g. amino acids G12, G13, Q61) and NRAS (e.g. amino acids G12, G13,Q61, A146) are also found in a variety of human cancer types howevertypically at a lower frequency compared to KRAS mutations (Cox et al.,Nat. Rev. Drug Discov., 2014, 13(11):828-51). Alterations (e.g.mutation, over-expression, gene amplification) in Ras familyproteins/Ras genes have also been described as a resistance mechanismagainst cancer drugs such as the EGFR antibodies cetuximab andpanitumumab (Leto et al., J. Mol. Med. (Berl). 2014 July; 92(7):709-22)and the EGFR tyrosine kinase inhibitor osimertinib/AZD9291 (Ortiz-Cuaranet al., Clin. Cancer Res., 2016, 22(19):4837-47; Eberlein et al., CancerRes., 2015, 7 5(12):2489-500).

Glycine to cysteine mutations at residue 12 of Ras family proteins (theG12C mutation, e.g. KRAS G12C, NRAS G12C and HRAS G12C) is generatedfrom a G.C to T.A base transversion at codon 12, a mutation commonlyfound in RAS genes that accounts for 14% of all KRAS, 2% of all NRAS and2% of all HRAS mutations across cancer types. The G12C mutation isparticularly enriched in KRAS mutant non-small cell lung cancer withapproximately half carrying this mutation, which has been associatedwith the DNA adducts formed by tobacco smoke. The G12C mutation is notexclusively associated with lung cancer and is found in other RAS mutantcancer types including, e.g., 3-5% of all KRAS mutant colorectal cancer.

Inhibitors of such G12C mutant Ras family proteins which are capable tocovalently bind to these proteins, e.g. covalent binders to KRAS G12C,NRAS G12C and HRAS G12C, are expected to inhibit signaling in cellsdownstream of Ras family proteins (e.g. ERK phosphorylation). In cancercells associated with dependence on mutant Ras family proteins (e.g.KRAS mutant cancer cell lines), such binders/inhibitors are expected todeliver anti-cancer efficacy (e.g. inhibition of proliferation,survival, metastasis etc.).

To date there have been no inhibitors of G12C mutant Ras family proteinswhich have been approved for therapeutic use. Recently the firstselective drugs against KRAS G12C have moved into clinical developmentwith sotorasib and adagrasib already in advanced stage for the treatmentof KRAS G12C driven lung cancers (see corresponding patent applicationsWO 2018/217651, WO 2017/201161, WO 2019/099524, WO 2020/102730). Thereis a need for new or even improved inhibitors of G12C mutant Ras familyproteins suitable for clinical use.

DETAILED DESCRIPTION OF THE INVENTION

Compounds

It has now been found that, surprisingly, compounds of formula (I)wherein R^(1a), R^(1b), R^(2a), R^(2b), Z, R³, R⁵, A, p, U, V, W, L andE have the meanings given hereinafter act as inhibitors of G12C mutantRas family proteins which are involved in controlling cell proliferationand possess anti-tumor activity, being useful in inhibiting theuncontrolled cellular proliferation which arises from malignant disease.It is believed that this anti-tumor activity is derived from inhibitionof G12C mutant Ras family proteins, in particular KRAS G12C, that arekey mediators of proliferation and survival in certain tumor cells. Itis further believed that the compounds according to the inventioninteract with, and then covalently bind to, G12C mutant Ras familyproteins, in particular KRAS G12C, via an electrophilic moiety (e.g. aMICHAEL acceptor) present in compounds of formula (I) (confirmed bymeans of crystallography for KRAS G12C). In covalently binding to G12Cmutant Ras family proteins, in particular KRAS G12C, which most probablyoccurs at position 12 of the Ras family proteins, the compounds impairor substantially eliminate the ability of the G12C Ras family proteinsto access their active, pro-proliferative/pro-survival conformation.

Indeed, the binding of the compounds of formula (I) according to theinvention may lead to selective and very strong antiproliferativecellular effects in G12C mutant KRAS cell lines and large selectivitywindows compared to KRAS wild type cells. This excellent potency canpotentially lead to lower systemic exposures and/or doses needed forfull efficacy in humans and therefore to good/better tolerability (e.g.a lower risk of idiosyncratic toxicities), may allow to hit the pathwayharder if necessary and may also turn out to be beneficial and bringincreased flexibility in case of combination treatments. The compoundsshow strong biomarker modulation, e.g. pERK in G12C mutant KRAS celllines. Selected compounds were tested in selectivity panels and showgood selectivity against other human targets, e.g. kinases. Last but notleast, selected compounds disclosed herein were tested and show goodpermeability, excellent solubility and have fine-tuned PK properties.

Thus, in a first aspect, the present invention relates to a compound offormula (I)

wherein

[A0]

R^(1a) and R^(1b) are both independently selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,C₁₋₄haloalkoxy, halogen, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,C₃₋₅cycloalkyl and 3-5 membered heterocyclyl;

R^(2a) and R^(2b) are both independently selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,C₁₋₄haloalkoxy, halogen, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,C₃₋₅cycloalkyl and 3-5 membered heterocyclyl; and/or, optionally, one ofR^(1a) or R^(1b) and one of R^(2a) or R^(2b) together with the carbonatoms they are attached form a cyclopropane ring;

[B0]

Z is —(CR^(6a)R^(6b))_(n)—;

each R^(6a) and R^(6b) is independently selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,C₁₋₄haloalkoxy, halogen, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,C₃₋₅cycloalkyl and 3-5 membered heterocyclyl;

-   -   n is selected from the group consisting 0, 1 and 2;

[C0]

R³ is selected from the group consisting of hydrogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, cyano-C₁₋₆alkyl, halogen,—OH, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CN, C₃₋₅cycloalkyl and 3-5membered heterocyclyl;

[D0]

ring A is a an oxadiazole or a thiadiazole;

[E0]

U is selected from the group consisting of nitrogen (═N—) and carbonsubstituted with R^(A)(═C(R^(A))—);

V is selected from the group consisting of nitrogen (═N—) and carbonsubstituted with R^(B) (═C(R^(B))—);

W is selected from the group consisting of nitrogen (═N—) and carbonsubstituted with R^(C) (═C(R^(C))—);

R^(A), R^(B) and R^(C) is each independently selected from the groupconsisting of hydrogen, C₁₋₆haloalkyl, C₂₋₆alkynyl optionallysubstituted with C₃₋₅cycloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, halogen,—CN, —OH, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —C(═O)NH₂,—C(═O)NH(C₁₋₄alkyl), —C(═O)N(C₁₋₄alkyl)₂, —S—C₁₋₆alkyl,—S(═O)₂—C₁₋₆alkyl, C₃₋₅cycloalkyl, 3-5 membered heterocyclyl andC₁₋₆alkyl optionally substituted with a substituent selected from thegroup consisting of C₁₋₆alkoxy, —CN, —OH, —NH₂, —NH(C₁₋₄alkyl),—N(C₁₋₄alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl) and —C(═O)N(C₁₋₄alkyl)₂;

[F0]

R⁵ is selected from the group consisting of R^(a1) and R^(b1);

-   -   R^(a1) is selected from the group consisting of C₁₋₆alkyl,        C₁₋₆haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl,        C₄₋₁₀cycloalkenyl, 3-11 membered heterocyclyl, C₆₋₁₀aryl and        5-10 membered heteroaryl, wherein the C₁₋₆alkyl, C₁₋₆haloalkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl,        3-11 membered heterocyclyl, C₆₋₁₀aryl and 5-10 membered        heteroaryl are all optionally substituted with one or more,        identical or different R^(b1) and/or R^(c1);    -   each R^(b1) is independently selected from the group consisting        of —OR^(c1), —NR^(c1)R^(c1), halogen, —CN, —C(═O)R^(c1),        —C(═O)OR^(c1), —C(═O)NR^(c1)R^(c1), —S(═O)₂R^(c1),        —S(═O)₂NR^(c1)R^(c1), —NHC(═O)R^(c1), —N(C₁₋₄alkyl)C(═O)R^(c1),        —NHS(═O)₂R^(c1), —N(C₁₋₄alkyl)S(═O)₂R^(c1), —NHC(═O)OR^(c1),        —N(C₁₋₄alkyl)C(═O)OR^(c1) and the bivalent substituent ═O; each        R^(c1) is independently selected from the group consisting of        hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, 3-11 membered heterocyclyl,        C₆₋₁₀aryl and 5-10 membered heteroaryl, wherein the C₁₋₆alkyl,        C₁₋₆haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl,        C₄₋₁₀cycloalkenyl, 3-11 membered heterocyclyl, C₆₋₁₀aryl and        5-10 membered heteroaryl are all optionally substituted with one        or more, identical or different R^(d1) and/or R^(e1);    -   each R^(d1) is independently selected from the group consisting        of —OR^(e1), —NR^(e1)R^(e1), halogen, —CN, —C(═O)R^(e1),        —C(═O)OR^(e1), —C(═O)NR^(e1)R^(e1), —S(═O)₂R^(e1),        —S(═O)₂NR^(e1)R^(e1), —NHC(═O)R^(e1), —N(C₁₋₄alkyl)C(═O)R^(e1),        —NHS(═O)₂R^(c1), —N(C₁₋₄alkyl)S(═O)₂R^(c1), —NHC(═O)OR^(e1),        —N(C₁₋₄alkyl)C(═O)OR^(e1) and the bivalent substituent ═O;    -   each R^(e1) is independently selected from the group consisting        of hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, 3-11 membered heterocyclyl,        C₆₋₁₀aryl and 5-10 membered heteroaryl, wherein the C₁₋₆alkyl,        C₁₋₆haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl,        C₄₋₁₀cycloalkenyl, 3-11 membered heterocyclyl, C₆₋₁₀aryl and        5-10 membered heteroaryl are all optionally substituted with one        or more, identical or different substituent(s) selected from the        group consisting of C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,        3-11 membered heterocyclyl optionally substituted with one or        more, identical or different C₁₋₄alkyl, C₆₋₁₀aryl, 5-10 membered        heteroaryl, —OH, C₁₋₆alkoxy, C₁₋₄alkoxy-C₁₋₄alkyl,        hydroxy-C₁₋₄alkyl, halogen, —CN, —NH₂, —C(═O)C₁₋₄alkyl,        —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂ and the bivalent substituent ═O;

[G0]

L is -L¹-L²-L³-, wherein L¹ is linked to E;

L¹ is selected from the group consisting of a bond, —NH—,—N(C₁₋₄alkyl)-, —O—, —C(═O)—, —NH—C(═O)—, —N(C₁₋₄alkyl)-C(═O)—,—C(═O)—NH—, —C(═O)—N(C₁₋₄alkyl)-, —C(═O)—, C₁₋₆alkylen,C₃₋₇cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10membered heteroarylene;

L² is selected from the group consisting of C₁₋₆alkylen,C₃₋₇cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10membered heteroarylene;

L³ is selected from the group consisting of a bond, —NH—,—N(C₁₋₄alkyl)-, —O—, —C(═O)—, —NH—C(═O)—, —N(C₁₋₄alkyl)-C(═O)—,—C(═O)—NH—, —C(═O)—N(C₁₋₄alkyl)-, —C(═O)—, C₁₋₆alkylen,C₃₋₇cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10membered heteroarylene;

wherein each C₁₋₆alkylen, C₃₋₇cycloalkylene, phenylene, 4-12 memberedheterocyclylene and 5-10 membered heteroarylene in L¹, L² and L³ isoptionally and independently substituted with one or more, identical ordifferent substituent(s) selected from the group consisting ofC₂₋₆alkinyl, C₁₋₆haloalkyl, C₃₋₇cycloalkyl, phenyl, 5-6 memberedheteroaryl, halogen, —OH, —CN, C₁₋₆alkoxy, —NH₂, —NH(C₁₋₄alkyl),—N(C₁₋₄alkyl)₂, —C(═O)OH, —C(═O)—OC₁₋₆alkyl, —C(═O)NH₂,—C(═O)NH(C₁₋₄alkyl), —C(═O)N(C₁₋₄alkyl)₂, the bivalent substituent ═Oand C₁₋₆alkyl optionally substituted with one or more, identical ordifferent substituent(s) selected from the group consisting of halogen,—OH, —CN, C₁₋₄alkoxy, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —C(═O)OH,—C(═O)—OC₁₋₆alkyl, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl) and—C(═O)N(C₁₋₄alkyl)₂;

[H0]

E is

represents a double or a triple bond;

Q¹ is selected from the group consisting of a bond, —CH₂—, —CH(OH)—,—C(═O)—, —C(═O)N(R^(G1))—, —C(═O)O—, —S(═O)₂—, —S(═O)₂N(R^(G1))— and—C(═NR^(H1))—;

each R^(G1) is independently selected from the group consisting ofhydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, hydroxy-C₁₋₆alkyl, H₂N—C₁₋₆alkyl,cyano-C₁₋₆alkyl, (C₁₋₄alkyl)HN—C₁₋₆alkyl, (C₁₋₄alkyl)₂N—C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl, C₃₋₇cycloalkyl and 3-11 membered heterocyclyl;each R^(H1) is independently selected from the group consisting ofhydrogen, —OH, C₁₋₆alkoxy, —CN and C₁₋₆alkyl; if

represents a double bond then

-   -   R^(D) is selected from the group consisting of hydrogen,        C₃₋₇cycloalkyl, phenyl, halogen, —CN, C₁₋₆alkoxy,        —C(═O)O—C₁₋₆alkyl, —NHC(═O)—C₁₋₆alkyl and C₁₋₆alkyl optionally        substituted with one or more, identical or different        substituent(s) selected from the group consisting of phenyl,        3-11 membered heterocyclyl, C₁₋₆alkoxy, halogen, —OH, —NH₂,        —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C(═O)OH, —C(═O)O—C₁₋₆alkyl,        —C(═O)NH(C₁₋₆alkyl), —NHC(═O)—C₁₋₆alkyl, —OC(═O)—C₁₋₆alkyl and        phenyl-C₁₋₆alkoxy;    -   R^(E) and R^(F) is each independently selected from the group        consisting of R^(a2) and R^(b2);    -   R^(a2) is selected from the group consisting of hydrogen,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11 membered        heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl, wherein        the C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11 membered        heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are all        optionally substituted with one or more, identical or different        R^(b2) and/or R^(c2);    -   each R^(b2) is independently selected from the group consisting        of —OR^(c2), —NR^(c2)R^(c2), halogen, —CN, —C(═O)R^(c2),        —C(═O)OR^(c2), —C(═O)NR²R^(c2), —S(═O)₂R^(c2),        —S(═O)₂NR^(c2)R^(c2), —NHC(═O)R^(c2), —N(C₁₋₄alkyl)C(═O)R^(c2),        —NHC(═O)OR^(c2), —N(C₁₋₄alkyl)C(═O)OR^(c2) and the bivalent        substituent ═O;    -   each R^(c2) is independently selected from the group consisting        of hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, 3-11 membered heterocyclyl,        C₆₋₁₀aryl and 5-10 membered heteroaryl, wherein the C₁₋₆alkyl,        C₁₋₆haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl,        C₄₋₁₀cycloalkenyl, 3-11 membered heterocyclyl, C₆₋₁₀aryl and        5-10 membered heteroaryl are all optionally substituted with one        or more, identical or different substituent(s) selected from the        group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen, —OH,        —C(═O)OH, —C(═O)O—C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, —C(═O)NH₂,        —C(═O)NH(C₁₋₆alkyl), —C(═O)N(C₁₋₆alkyl)₂, and the bivalent        substituent ═O;    -   or    -   R^(D) and R^(E) taken together with the carbon atoms they are        attached form a 4-7 membered unsaturated alicycle or 4-7        membered unsaturated heterocycle, wherein this 4-7 membered        unsaturated alicycle or 4-7 membered unsaturated heterocycle is        optionally, in addition to R^(F), substituted with one or more        identical or different substituent(s) selected from the group        consisting of C₁₋₆alkyl, C₁₋₆haloalkyl, —OH, C₁₋₆alkoxy,        C₁₋₄alkoxy-C₁₋₄alkyl, —NH₂, —CN, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,        halogen, —C(═O)O—C₁₋₆alkyl and the bivalent substituent ═O;    -   or    -   if Q¹ is —C(═O)N(R^(G1))—, then R^(G1) of —C(═O)N(R^(G1))— and        R^(F) together form a linker selected from the group consisting        of —C(═O)—, —CH₂—, —CH₂—C(═O)—, —C(═O)—CH₂— and —C₂H₄—;

if

represents a triple bond then

-   -   R^(D) and R^(E) are both absent    -   R^(F) is R^(a2)    -   R^(a2) is selected from the group consisting of hydrogen,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11 membered        heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl, wherein        the C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11 membered        heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are all        optionally substituted with one or more, identical or different        R^(b2) and/or R^(c2);    -   each R^(b2) is independently selected from the group consisting        of —OR^(c2), —NR^(c2)R^(c2), halogen, —CN, —C(═O)R^(c2),        —C(═O)OR^(c2), —C(═O)NR^(c2)R^(c2), —S(═O)₂R^(c2),        —S(═O)₂NR^(c2)R^(c2), —NHC(═O)R^(c2), —N(C₁₋₄alkyl)C(═O)R^(c2),        —NHC(═O)OR^(c2), —N(C₁₋₄alkyl)C(═O)OR^(c2) and the bivalent        substituent ═O;    -   each R^(c2) is independently selected from the group consisting        of hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11        membered heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl;

or

E is

Q² is selected from the group consisting of a bond, —CH₂—, —CH(OH)—,—C(═O)—, —C(═O)N(R^(G2))—, —C(═O)O—, —S(═O)₂—, —S(═O)₂N(R^(G2))— and—C(═NR^(H2))—;

each R^(G2) is independently selected from the group consisting ofhydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, hydroxy-C₁₋₆alkyl, H₂N—C₁₋₆alkyl,cyano-C₁₋₆alkyl, (C₁₋₄alkyl)HN—C₁₋₆alkyl, (C₁₋₄alkyl)₂N—C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl, C₃₋₇cycloalkyl and 3-11 membered heterocyclyl;each R^(H2) is independently selected from the group consisting ofhydrogen, —OH, C₁₋₆alkoxy, —CN and C₁₋₆alkyl;

R^(I) is selected from the group consisting of hydrogen and halogen;

R^(J) is hydrogen; or

R^(I) and R^(J) together with the carbon atoms they are attached form acyclopropane or oxirane ring;

R^(K) is selected from the group consisting of hydrogen, C₁₋₆alkyl, —CNand halogen;

R^(L) is selected from the group consisting of hydrogen, C₁₋₆alkyl, —CN,halogen and —C(═O)—C₁₋₆alkyl;

or

E is

Q³ is selected from the group consisting of —C(═O)—, —C(═O)N(R^(G3))—,—C(═O)O—, —S(═O)₂—, —S(═O)₂N(R^(G3))— and —C(═NR^(H3))—;

each R^(G3) is independently selected from the group consisting ofhydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, hydroxy-C₁₋₆alkyl, H₂N—C₁₋₆alkyl,cyano-C₁₋₆alkyl, (C₁₋₄alkyl)HN—C₁₋₆alkyl, (C₁₋₄alkyl)₂N—C₁₋₆alkyl,C₁₋₆alkoxy-C₁₋₆alkyl, C₃₋₇cycloalkyl and 3-11 membered heterocyclyl;

each R^(H3) is independently selected from the group consisting ofhydrogen, —OH, C₁₋₆alkoxy, —CN and C₁₋₆alkyl;

R^(M) is selected from the group consisting of halogen, —CN and—O—C(═O)—C₁₋₆alkyl;

or

E is

Q⁴ is selected from the group consisting of a bond, —C(═O)—, —C(═O)O—,—C(═O)NH—, —C(═O)N(C₁₋₄alkyl)-, —S(═O)₂— and —S(═O)₂NH—;

ring B is selected from the group consisting of phenyl, pyridyl,pyrimidyl, pyridazinyl, pyrazinyl and 5-membered heteroaryl;

q is selected from the group consisting 1, 2, 3 and 4;

each R^(N) is independently selected from the group consisting ofC₁₋₄alkyl, C₁₋₄haloalkyl, vinyl, ethinyl, halogen, —CN, nitro andC₁₋₄alkoxy;

or a salt thereof.

In a second aspect, the present invention relates to a compound offormula (I*) or a salt thereof

wherein

R^(1a), R^(1b), R^(2a), R^(2b), Z, R³, ring A, U, V, W, R⁵, L and E aredefined as in formula (I) in the first aspect.

In a third aspect, the present invention relates to a compound offormula (Ia) or a salt thereof

wherein

R^(1a), R^(1b), R^(2a), R^(2b), Z, R³, U, V, W, R⁵, L and E are definedas in formula (I) in the first aspect.

In a fourth aspect, the present invention relates to a compound offormula (Ia*) or a salt thereof

wherein

R^(1a), R^(1b), R^(2a), R^(2b), Z, R³, U, V, W, R⁵, L and E are definedas in formula (I) in the first aspect.

It is to be understood that compounds (I*), (Ia) and (Ia*) each are asubset of compounds (I) and that whenever it is referred to compounds(I) this is meant to also refer to and include compounds (I*), (Ia) and(Ia*) unless stated otherwise.

It is to be understood that compounds (Ia*) are a subset of therespective compounds (Ia), and that whenever it is referred to compounds(Ia) this is meant to also refer to and include compounds (Ia*) unlessstated otherwise.

The following structural aspects represent preferred embodiments [A1] to[A3], [B1] to [B5], [C1] to [C5], [D1] to [D2], [E1] to [E9], [F1] to[F8], [G1] to [G3] and [H1] to [H8] of the corresponding structuralaspects [A0], [B0], [C0], [D0], [E0], [F0], [G0] and [H0], respectively.

In one aspect [A1] the invention relates to a compound of formula (I),(I*), (Ia) or (Ia*) or a salt thereof, wherein

R^(1a) and R^(1b) are both independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

R^(2a) and R^(2b) are both independently selected from the groupconsisting of hydrogen and halogen.

In another aspect [A2] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

R^(1a) and R^(1b) are both independently selected from the groupconsisting of hydrogen and methyl;

R^(2a) and R^(2b) are both independently selected from the groupconsisting of hydrogen and fluorine.

In another aspect [A3] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

R^(1a), R^(1b), R^(2a) and R^(2b) are hydrogen.

In another aspect [B1] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

Z is —(CR^(6a)R^(6b))_(n)—;

n is 0.

In another aspect [B2] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

Z is —(CR^(6a)R^(6b))_(n)—;

n is 1;

R^(6a) and R^(6b) are both independently selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,C₁₋₄haloalkoxy, halogen, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,C₃₋₅cycloalkyl and 3-5 membered heterocyclyl.

In another aspect [B3] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

Z is —CH₂—.

In another aspect [B4] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

Z is —(CR^(6a)R^(6b))_(n)—;

n is 2;

each R^(6a) and R^(6b) is independently selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,C₁₋₄haloalkoxy, halogen, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,C₃₋₅cycloalkyl and 3-5 membered heterocyclyl.

In another aspect [B5] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

Z is —CH₂—CH₂—.

In another aspect [C1] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

R³ is selected from the group consisting of hydrogen, C₁₋₄alkyl,C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄haloalkoxy, cyano-C₁₋₄alkyl, halogen,—OH, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂ and —CN.

In another aspect [C2] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

R³ is selected from the group consisting of hydrogen, methyl, ethyl,—CF₃, —CHF₂, methoxy, trifluormethoxy, cyanomethyl, —OH and —CN.

In another aspect [C3] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

R³ is hydrogen.

In another aspect [C4] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

R³ is C₁₋₄alkyl.

In another aspect [C5] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

R³ is methyl.

In another aspect [D1] the invention relates to a compound of formula(I) or (I*) or a salt thereof, wherein

ring A is selected from the group consisting of

In another aspect [D2] the invention relates to a compound of formula(I) or (I*) or a salt thereof, wherein

ring A is

In another aspect [E1] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

U is carbon substituted with R^(A) (═C(R^(A))—);

V is carbon substituted with R^(B) (═C(R^(B))—);

W is nitrogen (═N—);

R^(A) and R^(B) is each independently selected from the group consistingof hydrogen, C₁₋₆haloalkyl, C₂₋₆alkynyl optionally substituted withC₃₋₅cycloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, halogen, —CN, —OH, —NH₂,—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl),—C(═O)N(C₁₋₄alkyl)₂, C₃₋₅cycloalkyl, 3-5 membered heterocyclyl andC₁₋₆alkyl optionally substituted with a substituent selected from thegroup consisting of C₁₋₆alkoxy, —CN, —OH, —NH₂, —NH(C₁₋₄alkyl),—N(C₁₋₄alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl) and —C(═O)N(C₁₋₄alkyl)₂.

In another aspect [E2] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

U is ═CH—;

V is ═CH—;

W is nitrogen (═N—).

In another aspect [E3] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

U is carbon substituted with R^(A) (═C(R^(A))—);

V is carbon substituted with R^(B) (═C(R^(B))—);

W is carbon substituted with R^(C) (═C(R^(C))—);

R^(A), R^(B) and R^(C) is each independently selected from the groupconsisting of hydrogen, C₁₋₆haloalkyl, C₂₋₆alkynyl optionallysubstituted with C₃₋₅cycloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, halogen,—CN, —OH, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —C(═O)NH₂,—C(═O)NH(C₁₋₄alkyl), —C(═O)N(C₁₋₄alkyl)₂, C₃₋₅cycloalkyl, 3-5 memberedheterocyclyl and C₁₋₆alkyl optionally substituted with a substituentselected from the group consisting of C₁₋₆alkoxy, —CN, —OH, —NH₂,—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl) and—C(═O)N(C₁₋₄alkyl)₂.

In another aspect [E4] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

U is ═CH—;

V is ═CH—;

W is ═CH—.

In another aspect [E5] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

U is nitrogen (═N—);

V is carbon substituted with R^(B) (═C(R^(B))—);

W is nitrogen (═N—);

R^(B) is selected from the group consisting of hydrogen, C₁₋₆haloalkyl,C₂₋₆alkynyl optionally substituted with C₃₋₅cycloalkyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, halogen, —CN, —OH, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,—C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl), —C(═O)N(C₁₋₄alkyl)₂, C₃₋₅cycloalkyl, 3-5membered heterocyclyl and C₁₋₆alkyl optionally substituted with asubstituent selected from the group consisting of C₁₋₆alkoxy, —CN, —OH,—NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl) and—C(═O)N(C₁₋₄alkyl)₂.

In another aspect [E6] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

U is nitrogen (═N—);

V is ═CH—;

W is nitrogen (═N—).

In another aspect [E7] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

U is carbon substituted with R^(A) (═C(R^(A))—);

V is nitrogen (═N—);

W is nitrogen (═N—);

R^(A) is selected from the group consisting of hydrogen, C₁₋₆haloalkyl,C₂₋₆alkynyl optionally substituted with C₃₋₅cycloalkyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, halogen, —CN, —OH, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,—C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl), —C(═O)N(C₁₋₄alkyl)₂, C₃₋₅cycloalkyl, 3-5membered heterocyclyl and C₁₋₆alkyl optionally substituted with asubstituent selected from the group consisting of C₁₋₆alkoxy, —CN, —OH,—NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl) and—C(═O)N(C₁₋₄alkyl)₂.

In another aspect [E8] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

U is carbon substituted with R^(A) (═C(R^(A))—);

V is nitrogen (═N—);

W is nitrogen (═N—);

R^(A) is selected from the group consisting of hydrogen and halogen.

In another aspect [E9] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

U is nitrogen (═N—);

V is nitrogen (═N—);

W is nitrogen (═N—).

In another aspect [F1] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

R⁵ is selected from the group consisting of R^(a1) and R^(b1);

-   -   R^(a1) is selected from the group consisting of C₁₋₆alkyl,        C₁₋₆haloalkyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, 3-11 membered        heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl, wherein        the C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, 3-11        membered heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl        are all optionally substituted with one or more, identical or        different R^(b1) and/or R^(c1);    -   each R^(b1) is independently selected from the group consisting        of —OR^(c1), —NR^(c1)R^(c1), halogen, —CN, —C(═O)R^(c1),        —C(═O)OR^(c1), —C(═O)NR^(c1)R^(c1), —S(═O)₂R^(c1),        —S(═O)₂NR^(c1)R^(c1), —NHC(═O)R^(c1), —N(C₁₋₄alkyl)C(═O)R^(c1)        and the bivalent substituent ═O;    -   each R^(c1) is independently selected from the group consisting        of hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11        membered heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl,        wherein the C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11        membered heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl        are all optionally substituted with one or more, identical or        different R^(d1) and/or R^(e1);    -   each R^(d1) is independently selected from the group consisting        of —OR^(e1), —NR^(e1)R^(e1), halogen, —CN, —C(═O)R^(e1),        —C(═O)NR^(e1)R^(e1) and the bivalent substituent ═O;    -   each R^(e1) is independently selected from the group consisting        of hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11        membered heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl,        wherein the C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11        membered heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl        are all optionally substituted with one or more, identical or        different substituent(s) selected from the group consisting of        C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11 membered        heterocyclyl optionally substituted with one or more, identical        or different C₁₋₄alkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl,        —OH, C₁₋₆alkoxy, C₁₋₄alkoxy-C₁₋₄alkyl, hydroxy-C₁₋₄alkyl,        halogen, —CN, —NH₂, —C(═O)C₁₋₄alkyl, —NH(C₁₋₄alkyl),        —N(C₁₋₄alkyl)₂ and the bivalent substituent ═O.

In another aspect [F2] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

R⁵ is R^(a1)

-   -   R^(a1) is selected from the group consisting of 3-11 membered        heterocyclyl and 5-10 membered heteroaryl, wherein the 3-11        membered heterocyclyl and 5-10 membered heteroaryl are all        optionally substituted with one or more, identical or different        R^(b1) and/or R^(c1);    -   each R^(b1) is independently selected from the group consisting        of —OR^(c1), —NR^(c1)R^(c1), halogen, —C(═O)OR^(c1) and the        bivalent substituent ═O;    -   each R^(c1) is independently selected from the group consisting        of hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl and 3-11        membered heterocyclyl, wherein the C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₁₀cycloalkyl and 3-11 membered heterocyclyl are all        optionally substituted with one or more, identical or different        R^(d1) and/or R^(e1);    -   each R^(d1) is independently selected from the group consisting        of —OR^(e1), —NR^(e1)R^(e1) and halogen;    -   each R^(e1) is independently selected from the group consisting        of hydrogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-11 membered        heterocyclyl, wherein the C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-11        membered heterocyclyl are all optionally substituted with one or        more, identical or different substituent(s) selected from the        group consisting of C₁₋₆alkyl and 3-11 membered heterocyclyl        optionally substituted with one or more, identical or different        C₁₋₄alkyl.

In another aspect [F3] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

R⁵ is R^(a1) selected from the group consisting of

wherein

-   -   each R^(a1) is optionally substituted with one or more,        identical or different R^(b1) and/or R^(c1);    -   each R^(b1) is independently selected from the group consisting        of —OR^(c1), —NR^(c1)R^(c1), halogen, —C(═O)OR^(c1) and the        bivalent substituent ═O;    -   each R^(c1) is independently selected from the group consisting        of hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl and 3-11        membered heterocyclyl, wherein the C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₁₀cycloalkyl and 3-11 membered heterocyclyl are all        optionally substituted with one or more, identical or different        R^(d1) and/or R^(e1);    -   each R^(d1) is independently selected from the group consisting        of —OR^(e1), —NR^(e1)R^(e1) and halogen;    -   each R^(e1) is independently selected from the group consisting        of hydrogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-11 membered        heterocyclyl, wherein the C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-11        membered heterocyclyl are all optionally substituted with one or        more, identical or different substituent(s) selected from the        group consisting of C₁₋₆alkyl and 3-11 membered heterocyclyl        optionally substituted with one or more, identical or different        C₁₋₄alkyl.

In another aspect [F4] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

R⁵ is R^(a1) selected from the group consisting of

wherein

each R^(a1) is optionally substituted with one or more, identical ordifferent of

-   -   C₁₋₆alkyl optionally substituted with one or more, identical or        different substituent(s) selected from the group consisting of        C₃₋₆cycloalkyl, hydroxy, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,        C₁₋₄alkoxy and 3-7 membered heterocyclyl optionally substituted        with C₁₋₄alkyl;    -   C₃₋₆cycloalkyl optionally substituted with one or more,        identical or different halogen;    -   3-11 membered heterocyclyl optionally substituted with one or        more, identical or different substituent(s) selected from the        group consisting of C₁₋₄alkyl, C₃₋₆cycloalkyl and halogen; and    -   a substituent selected from the group consisting of halogen,        —C(═O)—OC₁₋₆alkyl, C₁₋₆haloalkyl, —OH, —NH₂, —NH(C₁₋₄alkyl),        —N(C₁₋₄alkyl)₂ and the bivalent substituent ═O.

In another aspect [F5] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

R⁵ is selected from the group consisting of

In another aspect [F6] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

R⁵ is R^(b1);

-   -   R^(b1) is independently selected from the group consisting of        —OR^(c1) and —NR^(c1)R^(c1);    -   each R^(c1) is independently selected from the group consisting        of hydrogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl, 3-11 membered        heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl, wherein        the C₁₋₆alkyl, C₃₋₁₀cycloalkyl, 3-11 membered heterocyclyl,        C₆₋₁₀aryl and 5-10 membered heteroaryl are all optionally        substituted with one or more, identical or different R^(d1)        and/or R^(e1);    -   each R^(d1) is independently selected from the group consisting        of —OR^(e1), —NR^(e1)R^(e1), halogen, —C(═O)R^(e1) and        —C(═O)NR^(e1)R^(e1);    -   each R^(e1) is independently selected from the group consisting        of hydrogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl, 3-11 membered        heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl, wherein        the C₁₋₆alkyl, C₃₋₁₀cycloalkyl, 3-11 membered heterocyclyl,        C₆₋₁₀aryl and 5-10 membered heteroaryl are all optionally        substituted with one or more, identical or different        substituent(s) selected from the group consisting of C₁₋₆alkyl,        C₁₋₆haloalkyl, 3-11 membered heterocyclyl optionally substituted        with one or more, identical or different C₁₋₄alkyl, C₁₋₆alkoxy,        halogen and the bivalent substituent ═O.

In another aspect [F7] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

R⁵ is R^(b1);

-   -   R^(b1) is —OR^(c1);    -   each R¹ is independently selected from the group consisting of        C₁₋₆alkyl, C₃₋₁₀cycloalkyl, and 3-11 membered heterocyclyl,        wherein the C₁₋₆alkyl, C₃₋₁₀cycloalkyl and 3-11 membered        heterocyclyl are all optionally substituted with one or more,        identical or different R^(d1) and/or R^(e1);    -   each R^(d1) is independently selected from the group consisting        of —NR^(e1)R^(e1) and halogen;    -   each R^(e1) is independently selected from the group consisting        of hydrogen, C₁₋₆alkyl and 3-11 membered heterocyclyl, wherein        the C₁₋₆alkyl and 3-11 membered heterocyclyl are all optionally        substituted with one or more, identical or different        substituent(s) selected from the group consisting of C₁₋₆alkyl        and 3-11 membered heterocyclyl optionally substituted with one        or more, identical or different C₁₋₄alkyl.

In another aspect [F8] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

R⁵ is selected from the group consisting of

In another aspect [G1] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

L is -L¹-L²-L³-, wherein L¹ is linked to E;

L¹ is selected from the group consisting of a bond, C₁₋₆alkylen and 4-12membered heterocyclylene;

L² is selected from the group consisting of C₁₋₆alkylen, phenylene and4-12 membered heterocyclylene;

L³ is selected from the group consisting of a bond, —NH—, —N(C₁₋₄alkyl)-and —O—;

wherein each C₁₋₆alkylen, phenylene and 4-12 membered heterocyclylene inL¹ and L² is optionally and independently substituted with one or more,identical or different substituent(s) selected from the group consistingof C₂₋₆alkinyl, C₁₋₆haloalkyl, C₃₋₇cycloalkyl, phenyl, 5-6 memberedheteroaryl, halogen, —OH, —CN, C₁₋₆alkoxy, —NH₂, —NH(C₁₋₄alkyl),—N(C₁₋₄alkyl)₂, —C(═O)OH, —C(═O)—OC₁₋₆alkyl, —C(═O)NH₂,—C(═O)NH(C₁₋₄alkyl), —C(═O)N(C₁₋₄alkyl)₂, the bivalent substituent ═Oand C₁₋₆alkyl optionally substituted with one or more, identical ordifferent substituent(s) selected from the group consisting of halogen,—OH, —CN, —NH₂, C₁₋₄alkoxy, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —C(═O)OH,—C(═O)—OC₁₋₆alkyl, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl) and—C(═O)N(C₁₋₄alkyl)₂.

In another aspect [G2] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

L is -L¹-L²-L³-, wherein L¹ is linked to E;

L¹ is selected from the group consisting of a bond, C₁₋₆alkylen and 4-12membered heterocyclylene;

L² is selected from the group consisting of C₁₋₆alkylen, phenylene and4-12 membered heterocyclylene;

L³ is selected from the group consisting of a bond, —NH—, —N(C₁₋₄alkyl)-and —O—;

wherein each C₁₋₆alkylen, phenylene and 4-12 membered heterocyclylene inL¹ and L² is optionally and independently substituted with one or more,identical or different C₁₋₆alkyl.

In another aspect [G3] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

L is selected from the group consisting of

In another aspect [H1] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

E is

Q¹ is selected from the group consisting of —CH₂—, —C(═O)—,—C(═O)N(R^(G1)), —C(═O)O—, —S(═O)₂—, —S(═O)₂N(R^(G1))— and—C(═NR^(H1))—;

each R^(G1) is independently selected from the group consisting ofhydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl and hydroxy-C₁₋₆alkyl;

each R^(H1) is independently selected from the group consisting ofhydrogen, —OH, C₁₋₆alkoxy, —CN and C₁₋₆alkyl;

R^(D) is selected from the group consisting of hydrogen, C₃₋₇cycloalkyl,phenyl, halogen, —CN, C₁₋₆alkoxy, —C(═O)O—C₁₋₆alkyl and C₁₋₆alkyloptionally substituted with one or more, identical or differentsubstituent(s) selected from the group consisting of phenyl, 3-11membered heterocyclyl, C₁₋₆alkoxy, halogen, —OH, —N(C₁₋₆alkyl)₂,—C(═O)OH, —C(═O)O—C₁₋₆alkyl, —C(═O)NH(C₁₋₆alkyl), —NHC(═O)—C₁₋₆alkyl,—OC(═O)—C₁₋₆alkyl and phenyl-C₁₋₆alkoxy;

R^(E) and R^(F) is each independently selected from the group consistingof R^(a2) and R^(b2);

-   -   R^(a2) is selected from the group consisting of hydrogen,        C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11 membered        heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl, wherein        the C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11 membered        heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are all        optionally substituted with one or more, identical or different        R^(b2) and/or R^(c2);    -   each R^(b2) is independently selected from the group consisting        of —OR^(c2), —NR^(c2)R^(c2), halogen, —CN, —C(═O)OR^(c2),        —C(═O)NR²R^(c2), —NHC(═O)R^(c2), —N(C₁₋₄alkyl)C(═O)R¹²,        —NHC(═O)OR^(c2) and —N(C₁₋₄alkyl)C(═O)OR¹²;    -   each R^(c2) is independently selected from the group consisting        of hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, 3-11 membered        heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl, wherein        the C₁₋₆alkyl, C₁₋₆haloalkyl, 3-11 membered heterocyclyl,        C₆₋₁₀aryl and 5-10 membered heteroaryl are all optionally        substituted with one or more, identical or different        substituent(s) selected from the group consisting of C₁₋₆alkyl,        C₁₋₆alkoxy, halogen, —OH, —C(═O)OH, —C(═O)O—C₁₋₆alkyl,        —C(═O)C₁₋₆alkyl, —C(═O)NH₂, —C(═O)NH(C₁₋₆alkyl),        —C(═O)N(C₁₋₆alkyl)₂, and the bivalent substituent ═O.

In another aspect [H2] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

E is

Q¹ is selected from the group consisting of —CH₂—, —C(═O)—, —C(═O)NH—and —C(═O)N(C₁₋₄alkyl)-;

R^(D) is selected from the group consisting of hydrogen, halogen andC₁₋₆alkyl;

R^(E) and R^(F) is each independently selected from the group consistingof R^(a2) and R^(b2);

-   -   R^(a2) is selected from the group consisting of hydrogen and        C₁₋₆alkyl, wherein the C₁₋₆alkyl, is optionally substituted with        one or more, identical or different R^(b2) and/or R^(c2)    -   each R^(b2) is independently selected from the group consisting        of —OR^(c2) and —C(═O)NR^(c2)R^(c2);    -   each R^(c2) is independently selected from the group consisting        of C₁₋₆alkyl and 3-11 membered heterocyclyl.

In another aspect [H3] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

E is selected from the group consisting of

In another aspect [H4] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

E is selected from the group consisting of

In another aspect [H5] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

E is

Q¹ is selected from the group consisting of —CH₂—, —C(═O)—,—C(═O)N(R^(G1)), —C(═O)O—, —S(═O)₂—, —S(═O)₂N(R^(G1))— and—C(═NR^(H1))—;

each R^(G1) is independently selected from the group consisting ofhydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl and hydroxy-C₁₋₆alkyl;

each R^(H1) is independently selected from the group consisting ofhydrogen, —OH, C₁₋₆alkoxy, —CN and C₁₋₆alkyl;

R^(F) is selected from the group consisting of hydrogen and C₁₋₆alkyloptionally substituted with a substituent selected from the groupconsisting of —OH, C₁₋₆alkoxy, —NH₂, —NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂.

In another aspect [H6] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

E is

Q¹ is selected from the group consisting of —C(═O)—, —C(═O)N(R^(G1))—,S(═O)₂— and —S(═O)₂N (R^(G1))—;

each R^(G1) is independently selected from the group consisting ofhydrogen and C₁₋₆alkyl;

R^(F) is selected from the group consisting of hydrogen and C₁₋₆alkyloptionally substituted with a substituent selected from the groupconsisting of —OH, C₁₋₆alkoxy, —NH₂, —NH(C₁₋₄alkyl) and —N(C₁₋₄alkyl)₂.

In another aspect [H7] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

E is selected from the group consisting of

In another aspect [H8] the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*) or a salt thereof, wherein

E is selected from the group consisting of

All above-mentioned structural aspects [A1] to [A3], [B1] to [B5], [C1]to [C5], [D1] and [D2], [E1] to [E9], [F1] to [F8], [G1] to [G3] and[H1] to [H8] are preferred embodiments of the corresponding structuralaspects [A0], [B0], [C0], [D0], [E0], [F0], [G0] and [H0], respectively.The structural aspects [A0] to [A3], [B0] to [B5], [C0] to [C5], [D0] to[03], [E0] to [E9], [F0] to [F8], [G0] to [G3] and [H0] to [H8] relatingto different molecular parts of the compounds of formula (I), (I*), (Ia)and (Ia*) according to the invention may be combined with one another asdesired in combinations [A][B][C][D][E][F][G][H] (for compounds offormula (I) and (I*)), and combinations [A][B][C][E][F][G][H] (forcompounds of formula (Ia) and (Ia*)) to obtain preferred compounds (I),(I*), (Ia) and (Ia*). Each such combination [A][B][C][D][E][F][G][H]represents and defines individual embodiments or generic subsets ofcompounds (I) and (I*) according to the invention. Each such combination[A][B][C][E][F][G][H] represents and defines individual embodiments orgeneric subsets of compounds (Ia) and (Ia*) according to the invention.

Preferred embodiments of the invention of formula (Ia) are examplecompounds Ia-1 to Ia-170 and any subset thereof.

The present invention further relates to hydrates, solvates, polymorphs,metabolites, derivatives, stereoisomers and prodrugs of a compound offormula (I), (I*), (Ia) and (Ia*) (including all its embodiments).

The present invention further relates to a hydrate of a compound offormula (I), (I*), (Ia) and (Ia*) (including all its embodiments).

The present invention further relates to a solvate of a compound offormula (I), (I*), (Ia) and (Ia*) (including all its embodiments).

Compounds of formula (I), (I*), (Ia) and (Ia*) (including all itsembodiments) which e.g. bear ester groups are potential prodrugs theester being cleaved under physiological conditions and are also part ofthe invention.

The present invention further relates to a pharmaceutically acceptablesalt of a compound of formula (I), (I*), (Ia) and (Ia*) (including allits embodiments).

The present invention further relates to a pharmaceutically acceptablesalt of a compound of formula (I), (I*), (Ia) and (Ia*) (including allits embodiments) with anorganic or organic acids or bases.

Intermediates

In a fifth aspect, the present invention relates to a compound offormula (II) or a salt thereof

wherein

R^(1a), R^(1b), R^(2a), R^(2b), Z, R³, ring A, U, V, W, R⁵ and L aredefined as in formula (I) in the first aspect.

Compounds of formula (II) are intermediates in the synthesis ofcompounds of formula (I) (the hydrogen in residue H-L- isreplaced/substituted by group E in the last synthetic step).

In a sixth aspect, the present invention relates to a compound offormula (II*) or a salt thereof

wherein

R^(1a), R^(1b), R^(2a), R^(2b), Z, R³, ring A, U, V, W, R⁵ and L aredefined as in formula (I) in the first aspect.

In a seventh aspect, the present invention relates to a compound offormula (B-5) or a salt thereof

wherein

R^(1a), R^(1b), R^(2a), R^(2b), Z, R³, U, V, W, R⁵ and L are defined asin formula (I) in the first aspect.

In an eighth aspect, the present invention relates to a compound offormula (B-5*) or a salt thereof

wherein

R^(1a), R^(1b), R^(2a), R^(2b), Z, R³, U, V, W, R⁵ and L are defined asin formula (I) in the first aspect.

It is to be understood that compounds (II*), (B-5) and (B-5*) each are asubset of compounds (II) and that whenever it is referred to compounds(II) this is meant to also refer to and include compounds (II*), (B-5)and (B-5*) unless stated otherwise.

It is to be understood that compounds (B-5*) are a subset of therespective compounds (B-5) and that whenever it is referred to compounds(B-5) this is meant to also refer to and include compounds (B-5*) unlessstated otherwise.

All above-mentioned structural aspects [A1] to [A3], [B1] to [B5], [C1]to [C5], [D1] and [D2], [E1] to [E9], [F1] to [F8] and [G1] to [G3]disclosed as preferred embodiments of the corresponding structuralaspects [A0], [B0], [C0], [D0], [E0], [F0] and [G0] of compounds offormula (I), (I*), (Ib), (Ib*), (Ic), (Ic*), (Id), (Id*), (Ie) and (Ie*)are also the preferred embodiments of the corresponding structuralaspects [A0], [B0], [C0], [D0], [E0], [F0] and [G0] of compounds offormula (II), (II*), (B-5) and (B-5*).

Thus, these structural aspects [A0] to [A3], [B0] to [B5], [C0] to [C5],[D0] to [D2], [E0] to [E9], [F0] to [F8] and [G0] to [G3] relating todifferent molecular parts of the compounds of formula (II), (II*), (B-5)and (B-5*) may be combined with one another as desired in combinations[A][B][C][D][E][F][G] (for compounds of formula (II) and (II*)) andcombinations [A][B][C][E][F][G] (for compounds of formula (B-5) and(B-5*)) to obtain preferred compounds of formula (II), (II*), (B-5) and(B-5*). Each such combination [A][B][C][D][E][F][G] represents anddefines individual embodiments or generic subsets of compounds offormula (II) and (II*). Each such combination [A][B][C][E][F][G]represents and defines individual embodiments or generic subsets ofcompounds of formula (B-5) and (B-5*).

Pharmaceutical Compositions

Suitable pharmaceutical compositions for administering the compounds offormula (I), (I*), (Ia) or (Ia*) according to the invention will beapparent to those with ordinary skill in the art and include for exampletablets, pills, capsules, suppositories, lozenges, troches,solutions—particularly solutions for injection (s.c., i.v., i.m.) andinfusion (injectables)—elixirs, syrups, sachets, emulsions, inhalativesor dispersible powders. The content of the compounds (I), (I*), (Ia) or(Ia*) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50wt.-% of the composition as a whole, i.e. in amounts which aresufficient to achieve the dosage range specified below. The dosesspecified may, if necessary, be given several times a day.

Suitable tablets may be obtained, for example, by mixing the compounds(I), (I*), (Ia) or (Ia*) with known pharmaceutically acceptableexcipients, for example inert diluents, carriers, disintegrants,adjuvants, surfactants, binders and/or lubricants. The tablets may alsocomprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with excipients normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing one or more compounds (I), (I*), (Ia) or(Ia*) or combinations with one or more other pharmaceutically activesubstance(s) may additionally contain excipients like a sweetener suchas saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g.a flavouring such as vanillin or orange extract. They may also containexcipients like suspension adjuvants or thickeners such as sodiumcarboxymethyl cellulose, wetting agents such as, for example,condensation products of fatty alcohols with ethylene oxide, orpreservatives such as p-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g.with the addition of excipients like isotonic agents, preservatives suchas p-hydroxybenzoates, or stabilisers such as alkali metal salts ofethylenediamine tetraacetic acid, optionally using emulsifiers and/ordispersants, whilst if water is used as the diluent, for example,organic solvents may optionally be used as solvating agents ordissolving aids, and transferred into injection vials or ampoules orinfusion bottles.

Capsules containing one or more compounds (I), (I*), (Ia) or (Ia*) orcombinations with one or more other pharmaceutically active substance(s)may for example be prepared by mixing the compounds/active substance(s)with inert excipients such as lactose or sorbitol and packing them intogelatine capsules.

Suitable suppositories may be made for example by mixing with excipientsprovided for this purpose such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

The pharmaceutical compositions are administered by the usual methods,preferably by oral or transdermal route, most preferably by oral route.For oral administration the tablets may of course contain, apart fromthe above-mentioned excipients, additional excipients such as sodiumcitrate, calcium carbonate and dicalcium phosphate together with variousexcipients such as starch, preferably potato starch, gelatine and thelike. Moreover, lubricants such as magnesium stearate, sodium laurylsulphate and talc may be used at the same time for the tablettingprocess. In the case of aqueous suspensions the active substances may becombined with various flavour enhancers or colourings in addition to theexcipients mentioned above.

For parenteral use, solutions of the active substances with suitableliquid excipients may be used.

The dosage range of the compounds of formula (I), (I*), (Ia) or (Ia*)applicable per day is usually from 1 mg to 2000 mg, preferably from 250to 1250 mg.

However, it may sometimes be necessary to depart from the amountsspecified, depending on the body weight, age, the route ofadministration, severity of the disease, the individual response to thedrug, the nature of its formulation and the time or interval over whichthe drug is administered (continuous or intermittent treatment with oneor multiple doses per day). Thus, in some cases it may be sufficient touse less than the minimum dose given above, whereas in other cases theupper limit may have to be exceeded. When administering large amounts itmay be advisable to divide them up into a number of smaller doses spreadover the day.

Thus, in a further aspect the invention relates to a pharmaceuticalcomposition comprising at least one (preferably one) compound of formula(I), (I*), (Ia) or (Ia*)—or a pharmaceutically acceptable saltthereof—and one or more pharmaceutically acceptable excipient(s).

The compounds of formula (I), (I*), (Ia) or (Ia*)—or thepharmaceutically acceptable salts thereof—and the pharmaceuticalcompositions comprising such compound and salts may also beco-administered with other pharmacologically active substances, e.g.with other anti-neoplastic compounds (e.g. chemotherapy), i.e. used incombination (see combination treatment further below).

The elements of such combinations may be administered (whetherdependently or independently) by methods customary to the skilled personand as they are used in monotherapy, e.g. by oral, enterical, parenteral(e.g., intramuscular, intraperitoneal, intravenous, transdermal orsubcutaneous injection, or implant), nasal, vaginal, rectal, or topicalroutes of administration and may be formulated, alone or together, insuitable dosage unit formulations containing conventional non-toxicpharmaceutically acceptable excipients appropriate for each route ofadministration.

The combinations may be administered at therapeutically effective singleor divided daily doses. The active components of the combinations may beadministered in such doses which are therapeutically effective inmonotherapy, or in such doses which are lower than the doses used inmonotherapy, but when combined result in a desired (joint)therapeutically effective amount.

However, when the combined use of the two or more active substances orprinciples leads to a synergistic effect, it may also be possible toreduce the amount of one, more or all of the substances or principles tobe administered, while still achieving the desired therapeutic action.This may for example be useful for avoiding, limiting or reducing anyunwanted side-effects that are associated with the use of one or more ofthe substances or principles when they are used in their usual amounts,while still obtaining the desired pharmacological or therapeutic effect.

Thus, in a further aspect the invention also relates to a pharmaceuticalcomposition comprising a compound of formula (I), (I*), (Ia) or (Ia*)—ora pharmaceutically acceptable salt thereof—and one or more (preferablyone or two, most preferably one) other pharmacologically activesubstance(s).

In a further aspect the invention also relates to a pharmaceuticalpreparation comprising a compound of formula (I), (I*), (Ia) or (Ia*)—ora pharmaceutically acceptable salt thereof—and one or more (preferablyone or two, most preferably one) other pharmacologically activesubstance(s).

Pharmaceutical compositions to be co-administered or used in combinationcan also be provided in the form of a kit.

Thus, in a further aspect the invention also relates to a kit comprising

-   -   a first pharmaceutical composition or dosage form comprising a        compound of formula (I), (I*), (Ia) or (Ia*) and, optionally,        one or more pharmaceutically acceptable excipient(s), and    -   a second pharmaceutical composition or dosage form comprising        another pharmacologically active substance and, optionally, one        or more pharmaceutically acceptable excipient(s).

In one aspect such kit comprises a third pharmaceutical composition ordosage form comprising still another pharmacologically active substanceand, optionally, one or more pharmaceutically acceptable excipient(s).

Medical Uses—Methods of Treatment

Indications—patient populations

The present invention is mainly directed to RAS G12C inhibitors, inparticular compounds of formula (I), (I*), (Ia) and (Ia*) (including allits embodiments), which are potentially useful in the treatment and/orprevention of diseases and/or conditions mediated by RAS G12C mutations,e.g. and preferably KRAS G12C, NRAS G12C and HRAS G12C.

Thus, in a further aspect the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*)—or a pharmaceutically acceptable saltthereof—for use as a medicament.

In a further aspect the invention relates to a compound of formula (I),(I*), (Ia) or (Ia*)—or a pharmaceutically acceptable salt thereof—foruse in a method of treatment of the human or animal body.

In a further aspect the invention relates to a compound of formula (I),(I*), (Ia) or (Ia*)—or a pharmaceutically acceptable salt thereof—foruse in the treatment and/or prevention of a disease and/or conditionmediated by RAS G12C mutations.

In a further aspect the invention relates to the use of a compound offormula (I), (I*), (Ia) or (Ia*)—or a pharmaceutically acceptable saltthereof—in the manufacture of a medicament for the treatment and/orprevention of a disease and/or condition mediated by RAS G12C mutations.

In a further aspect the invention relates to a method for the treatmentand/or prevention of a disease and/or condition mediated by RAS G12Cmutations comprising administering a therapeutically effective amount ofa compound of formula (I), (I*), (Ia) or (Ia*)—or a pharmaceuticallyacceptable salt thereof—to a human being.

In a further aspect the invention relates to a compound of formula (I),(I*), (Ia) or (Ia*)—or a pharmaceutically acceptable salt thereof—foruse in the treatment and/or prevention of cancer.

In a further aspect the invention relates to a compound of formula (I),(I*), (Ia) or (Ia*)—or a pharmaceutically acceptable salt thereof—foruse in a method of treatment and/or prevention of cancer in the human oranimal body.

In a further aspect the invention relates to the use of a compound offormula (I), (I*), (Ia) or (Ia*)—or a pharmaceutically acceptable saltthereof—in the manufacture of a medicament for the treatment and/orprevention of cancer.

In a further aspect the invention relates to a method for the treatmentand/or prevention of cancer comprising administering a therapeuticallyeffective amount of a compound of formula (I), (I*), (Ia) or (Ia*)—or apharmaceutically acceptable salt thereof—to a human being.

In a further aspect the invention relates to a compound of formula (I),(I*), (Ia) or (Ia*)—or a pharmaceutically acceptable salt thereof—foruse in providing an inhibitory effect on G12C mutant RAS.

In a further aspect the invention relates to the use of a compound offormula (I), (I*), (Ia) or (Ia*)—or a pharmaceutically acceptable saltthereof—in the manufacture of a medicament for use in providing aninhibitory effect on G12C mutant RAS.

In a further aspect the invention relates to a method for providing aninhibitory effect on G12C mutant RAS comprising administering atherapeutically effective amount of a compound of formula (I), (I*),(Ia) or (Ia*)—or a pharmaceutically acceptable salt thereof—to a humanbeing.

Another aspect is based on identifying a link between the G12C mutationstatus of a patient and potential susceptibility to treatment with acompound of formula (I), (I*), (Ia) or (Ia*). A RAS G12C inhibitor, suchas a compound of formula (I), (I*), (Ia) or (Ia*), may thenadvantageously be used to treat patients with KRAS G12C, HRAS G12C orNRAS G12C mutations who may be resistant to other therapies. Thistherefore provides opportunities, methods and tools for selectingpatients for treatment with a compound of formula (I), (I*), (Ia) or(Ia*), particularly cancer patients. The selection is based on whetherthe tumor cells to be treated possess wild-type or G12C mutant KRAS,HRAS or NRAS gene. The G12C KRAS, HRAS or NRAS gene status couldtherefore be used as a biomarker to indicate that selecting treatmentwith a compound of formula (I), (I*), (Ia) or (Ia*) may be advantageous.

According to one aspect, there is provided a method for selecting apatient for treatment with a compound of formula (I), (I*), (Ia) or(Ia*), the method comprising

-   -   providing a tumor cell-containing sample from a patient;    -   determining whether the RAS gene in the patient's tumor        cell-containing sample encodes for wild-type (glycine at        position 12) or mutant (cysteine at position 12) KRAS, HRAS or        NRAS protein; and    -   selecting a patient for treatment with a compound of formula        (I), (I*), (Ia) or (Ia*) based thereon.

The method may include or exclude the actual patient sample isolationstep.

In one aspect, the patient is selected for treatment with a compound offormula (I), (I*), (Ia) or (Ia*) if the tumor cell DNA has a G12C mutantKRAS gene.

In another aspect, the patient is selected for treatment with a compoundof formula (I), (I*), (Ia) or (Ia*) if the tumor cell DNA has a G12Cmutant HRAS gene.

In another aspect, the patient is selected for treatment with a compoundof formula (I), (I*), (Ia) or (Ia*) if the tumor cell DNA has a G12Cmutant NRAS gene.

According to another aspect, there is provided a compound of formula(I), (I*), (Ia) or (Ia*)—or a pharmaceutically acceptable saltthereof—for use in treating a cancer with tumor cells harbouring a G12Cmutant RAS gene.

According to another aspect, there is provided a compound of formula(I), (I*), (Ia) or (Ia*)—or a pharmaceutically acceptable saltthereof—for use in treating a cancer with tumor cells harbouring a G12Cmutant KRAS gene.

According to another aspect, there is provided a compound of formula(I), (I*), (Ia) or (Ia*)—or a pharmaceutically acceptable saltthereof—for use in treating a cancer with tumor cells harbouring a G12Cmutant HRAS gene.

According to another aspect, there is provided a compound of formula(I), (I*), (Ia) or (Ia*)—or a pharmaceutically acceptable saltthereof—for use in treating a cancer with tumor cells harbouring a G12Cmutant NRAS gene.

According to another aspect, there is provided a method of treating acancer with tumor cells harbouring a G12C mutant RAS gene comprisingadministering an effective amount of a compound of formula (I), (I*),(Ia) or (Ia*)—or a pharmaceutically acceptable salt thereof—to a humanbeing.

According to another aspect, there is provided a method of treating acancer with tumor cells harbouring a G12C mutant KRAS, HRAS or NRAS genecomprising administering an effective amount of a compound of formula(I), (I*), (Ia) or (Ia*)—or a pharmaceutically acceptable salt thereof.

Determining whether a tumor or cancer comprises a G12C KRAS, HRAS orNRAS mutation can be undertaken by assessing the nucleotide sequenceencoding the KRAS, HRAS or NRAS protein, by assessing the amino acidsequence of the KRAS, HRAS or NRAS protein, or by assessing thecharacteristics of a putative KRAS, HRAS or NRAS mutant protein. Thesequence of wild-type human KRAS, HRAS or NRAS is known in the art.Methods for detecting a mutation in a KRAS, HRAS or NRAS nucleotidesequence are known by those of skill in the art. These methods include,but are not limited to, polymerase chain reaction-restriction fragmentlength polymorphism (PCR-RFLP) assays, polymerase chain reaction-singlestrand conformation polymorphism (PCR-SSCP) assays, real-time PCRassays, PCR sequencing, mutant allele-specific PCR amplification (MASA)assays, direct sequencing, primer extension reactions, electrophoresis,oligonucleotide ligation assays, hybridization assays, TaqMan assays,SNP genotyping assays, high resolution melting assays and microarrayanalyses. In some embodiments, samples are evaluated for G12C KRAS, HRASor NRAS mutations by real-time PCR. In real-time PCR, fluorescent probesspecific for the KRAS, HRAS or NRAS G12C mutation are used. When amutation is present, the probe binds and fluorescence is detected. Insome embodiments, the KRAS, HRAS or NRAS G12C mutation is identifiedusing a direct sequencing method of specific regions (e.g. exon 2 and/orexon 3) in the KRAS, HRAS or NRAS gene. This technique will identify allpossible mutations in the region sequenced. Methods for detecting amutation in a KRAS, HRAS or NRAS protein are known by those of skill inthe art. These methods include, but are not limited to, detection of aKRAS, HRAS or NRAS mutant using a binding agent (e.g. an antibody)specific for the mutant protein, protein electrophoresis, Westernblotting and direct peptide sequencing.

Methods for determining whether a tumor or cancer comprises a G12C KRAS,HRAS or NRAS mutation can use a variety of samples. In some embodiments,the sample is taken from a subject having a tumor or cancer. In someembodiments, the sample is a fresh tumor/cancer sample. In someembodiments, the sample is a frozen tumor/cancer sample. In someembodiments, the sample is a formalin-fixed paraffin-embedded sample. Insome embodiments, the sample is processed to a cell lysate. In someembodiments, the sample is processed to DNA or RNA. In some embodimentsthe sample is a liquid biopsy and the test is done on a sample of bloodto look for cancer cells from a tumor that are circulating in the bloodor for pieces of DNA from tumor cells that are in the blood.

The disease/condition/cancer/tumors/cancer cells to be treated/preventedwith a compound of formula (I), (I*), (Ia) or (Ia*)—or apharmaceutically acceptable salt thereof—according to the methods anduses as herein (above and below) defined and disclosed is selected fromthe group consisting of pancreatic cancer, lung cancer, colorectalcancer, cholangiocarcinoma, appendiceal cancer, multiple myeloma,melanoma, uterine cancer, endometrial cancer, thyroid cancer, acutemyeloid leukaemia, bladder cancer, urothelial cancer, gastric cancer,cervical cancer, head and neck squamous cell carcinoma, diffuse large Bcell lymphoma, oesophageal cancer, chronic lymphocytic leukaemia,hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer,glioblastoma, renal cancer and sarcomas.

In another aspect, the disease/condition/cancer/tumors/cancer cells tobe treated/prevented with a compound of formula (I), (I*), (Ia) or(Ia*)—or a pharmaceutically acceptable salt thereof—according to themethods and uses as herein (above and below) defined and disclosed isselected from the group consisting of pancreatic cancer, lung cancer(preferably non-small cell lung cancer (NSCLC)), cholangiocarcinoma andcolorectal cancer.

Particularly preferred, the cancer to be treated/prevented with acompound of formula (I), (I*), (Ia) or (Ia*)—or a pharmaceuticallyacceptable salt thereof—according to the methods and uses as herein(above and below) defined and disclosed is selected from the groupconsisting of:

-   -   lung adenocarcinoma (preferably non-small cell lung cancer        (NSCLC)) harboring a KRAS G12C mutation;    -   colorectal adenocarcinoma harboring a KRAS G12C mutation;    -   pancreatic adenocarcinoma (preferably pancreatic ductal        adenocarcinoma (PDAC)) harboring a KRAS G12C mutation.

Additionally, the following cancers, tumors and other proliferativediseases may be treated with compounds of formula (I), (I*), (Ia) or(Ia*)—or a pharmaceutically acceptable salt thereof—without beingrestricted thereto. Preferably, the methods of treatment, methods, uses,compounds for use and pharmaceutical compositions for use as disclosedherein (above and below) are applied in treatments ofdiseases/conditions/cancers/tumors which (i.e. the respective cells)harbour a RAS G12C mutation (preferably a KRAS G12C mutation) or havebeen identified to harbour a RAS G12C mutation (preferably a KRAS G12Cmutation) as herein described and/or referred:

cancers/tumors/carcinomas of the head and neck: e.g.tumors/carcinomas/cancers of the nasal cavity, paranasal sinuses,nasopharynx, oral cavity (including lip, gum, alveolar ridge, retromolartrigone, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx(including base of tongue, tonsil, tonsillar pilar, soft palate,tonsillar fossa, pharyngeal wall), middle ear, larynx (includingsupraglottis, glottis, subglottis, vocal cords), hypopharynx, salivaryglands (including minor salivary glands);

cancers/tumors/carcinomas of the lung: e.g. non-small cell lung cancer(NSCLC) (squamous cell carcinoma, spindle cell carcinoma,adenocarcinoma, large cell carcinoma, clear cell carcinoma,bronchioalveolar), small cell lung cancer (SCLC) (oat cell cancer,intermediate cell cancer, combined oat cell cancer);

neoplasms of the mediastinum: e.g. neurogenic tumors (includingneurofibroma, neurilemoma, malignant schwannoma, neurosarcoma,ganglioneuroblastoma, ganglioneuroma, neuroblastoma, pheochromocytoma,paraganglioma), germ cell tumors (including seminoma, teratoma,non-seminoma), thymic tumors (including thymoma, thymolipoma, thymiccarcinoma, thymic carcinoid), mesenchymal tumors (including fibroma,fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma,leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma,hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma,lymphangiopericytoma, lymphangiomyoma);

cancers/tumors/carcinomas of the gastrointestinal (GI) tract: e.g.tumors/carcinomas/cancers of the esophagus, stomach (gastric cancer),pancreas, liver and biliary tree (including hepatocellular carcinoma(HCC), e.g. childhood HCC, fibrolamellar HCC, combined HCC, spindle cellHCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC;hepatoblastoma; cholangiocarcinoma; cholangiocellular carcinoma; hepaticcystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma,malignant schwannoma, fibrosarcoma, Klatskin tumor), gall bladder,extrahepatic bile ducts, small intestine (including duodenum, jejunum,ileum), large intestine (including cecum, colon, rectum, anus;colorectal cancer, gastrointestinal stroma tumor (GIST)), genitourinarysystem (including kidney, e.g. renal pelvis, renal cell carcinoma (RCC),nephroblastoma (Wilms' tumor), hypernephroma, Grawitz tumor; ureter;urinary bladder, e.g. urachal cancer, urothelial cancer; urethra, e.g.distal, bulbomembranous, prostatic; prostate (androgen dependent,androgen independent, castration resistant, hormone independent, hormonerefractory), penis);

cancers/tumors/carcinomas of the testis: e.g. seminomas, non-seminomas,

gynecologic cancers/tumors/carcinomas: e.g. tumors/carcinomas/cancers ofthe ovary, fallopian tube, peritoneum, cervix, vulva, vagina, uterinebody (including endometrium, fundus);

cancers/tumors/carcinomas of the breast: e.g. mammary carcinoma(infiltrating ductal, colloid, lobular invasive, tubular, adenocystic,papillary, medullary, mucinous), hormone receptor positive breast cancer(estrogen receptor positive breast cancer, progesterone receptorpositive breast cancer), Her2 positive breast cancer, triple negativebreast cancer, Paget's disease of the breast;

cancers/tumors/carcinomas of the endocrine system: e.g.tumors/carcinomas/cancers of the endocrine glands, thyroid gland(thyroid carcinomas/tumors; papillary, follicular, anaplastic,medullary), parathyroid gland (parathyroid carcinoma/tumor), adrenalcortex (adrenal cortical carcinoma/tumors), pituitary gland (includingprolactinoma, craniopharyngioma), thymus, adrenal glands, pineal gland,carotid body, islet cell tumors, paraganglion, pancreatic endocrinetumors (PET; non-functional PET, PPoma, gastrinoma, insulinoma, VIPoma,glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumors;

sarcomas of the soft tissues: e.g. fibrosarcoma, fibrous histiocytoma,liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma,lymphangiosarcoma, Kaposi's sarcoma, glomus tumor, hemangiopericytoma,synovial sarcoma, giant cell tumor of tendon sheath, solitary fibroustumor of pleura and peritoneum, diffuse mesothelioma, malignantperipheral nerve sheath tumor (MPNST), granular cell tumor, clear cellsarcoma, melanocytic schwannoma, plexosarcoma, neuroblastoma,ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma,paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma,mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma,extrarenal rhabdoid tumor, desmoplastic small cell tumor; sarcomas ofthe bone: e.g. myeloma, reticulum cell sarcoma, chondrosarcoma(including central, peripheral, clear cell, mesenchymal chondrosarcoma),osteosarcoma (including parosteal, periosteal, high-grade surface, smallcell, radiation-induced osteosarcoma, Paget's sarcoma), Ewing's tumor,malignant giant cell tumor, adamantinoma, (fibrous) histiocytoma,fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma,hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma,eosinophilic granuloma, chondroblastoma;

mesothelioma: e.g. pleural mesothelioma, peritoneal mesothelioma;

cancers of the skin: e.g. basal cell carcinoma, squamous cell carcinoma,Merkel's cell carcinoma, melanoma (including cutaneous, superficialspreading, lentigo maligna, acral lentiginous, nodular, intraocularmelanoma), actinic keratosis, eyelid cancer; neoplasms of the centralnervous system and brain: e.g. astrocytoma (cerebral, cerebellar,diffuse, fibrillary, anaplastic, pilocytic, protoplasmic,gemistocytary), glioblastoma, gliomas, oligodendrogliomas,oligoastrocytomas, ependymomas, ependymoblastomas, choroid plexustumors, medulloblastomas, meningiomas, schwannomas, hemangioblastomas,hemangiomas, hemangiopericytomas, neuromas, ganglioneuromas,neuroblastomas, retinoblastomas, neurinomas (e.g. acoustic), spinal axistumors;

lymphomas and leukemias: e.g. B-cell non-Hodgkin lymphomas (NHL)(including small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma(LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuselarge cell lymphoma (DLCL), Burkitt's lymphoma (BL)), T-cell non-Hodgkinlymphomas (including anaplastic large cell lymphoma (ALCL), adult T-cellleukemia/lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheralT-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adultT-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunocytoma,chronic B-cell lymphocytic leukemia (B-CLL), chronic T-cell lymphocyticleukemia (T-CLL) B-cell small lymphocytic lymphoma (B-SLL), cutaneousT-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL),immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocytepredominance HD (NLPHD), nodular sclerosis HD (NSHD), mixed-cellularityHD (MCHD), lymphocyte-rich classic HD, lymphocyte-depleted HD (LDHD)),large granular lymphocyte leukemia (LGL), chronic myelogenous leukemia(CML), acute myelogenous/myeloid leukemia (AML), acutelymphatic/lymphoblastic leukemia (ALL), acute promyelocytic leukemia(APL), chronic lymphocytic/lymphatic leukemia (CLL), prolymphocyticleukemia (PLL), hairy cell leukemia, chronic myelogenous/myeloidleukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM),plasmacytoma, myelodysplastic syndromes (MDS), chronic myelomonocyticleukemia (CMML);

cancers of unknown primary site (CUP);

All cancers/tumors/carcinomas mentioned above which are characterized bytheir specific location/origin in the body are meant to include both theprimary tumors and the metastatic tumors derived therefrom.

All cancers/tumors/carcinomas mentioned above may be furtherdifferentiated by their histopathological classification:

Epithelial cancers, e.g. squamous cell carcinoma (SCC) (carcinoma insitu, superficially invasive, verrucous carcinoma, pseudosarcoma,anaplastic, transitional cell, lymphoepithelial), adenocarcinoma (AC)(well-differentiated, mucinous, papillary, pleomorphic giant cell,ductal, small cell, signet-ring cell, spindle cell, clear cell, oatcell, colloid, adenosquamous, mucoepidermoid, adenoid cystic), mucinouscystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, smallcell carcinoma, neuroendocrine tumors (small cell carcinoma,paraganglioma, carcinoid); oncocytic carcinoma;

Nonepithilial cancers, e.g. sarcomas (fibrosarcoma, chondrosarcoma,rhabdomyosarcoma, leiomyosarcoma, hemangiosarcoma, giant cell sarcoma,lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma,lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ celltumors, hematological neoplasms, mixed and undifferentiated carcinomas;

The compounds of the invention may be used in therapeutic regimens inthe context of first line, second line, or any further line treatments.

The compounds of the invention may be used for the prevention,short-term or long-term treatment of the above-mentioneddiseases/conditions/cancers/tumors, optionally also in combination withradiotherapy and/or surgery.

The methods of treatment, methods, uses and compounds for use asdisclosed herein (above and below) can be performed with any compound offormula (I), (I*), (Ia) or (Ia*)—or a pharmaceutically acceptable saltthereof—as disclosed or defined herein and with any pharmaceuticalcomposition or kit comprising a compound of formula (I), (I*), (Ia) or(Ia*)—or a pharmaceutically acceptable salt thereof (each including allindividual embodiments or generic subsets of compounds (1), (I*), (Ia)or (Ia*)).

Combination Treatment

The compounds of formula (I), (I*), (Ia) or (Ia*)—or thepharmaceutically acceptable salts thereof—and the pharmaceuticalcompositions comprising such compound and salts may also beco-administered with other pharmacologically active substances, e.g.with other anti-neoplastic compounds (e.g. chemotherapy), or used incombination with other treatments, such as radiation or surgicalintervention, either as an adjuvant prior to surgery orpost-operatively. Preferably, the pharmacologically active substance(s)for co-administration is/are (an) anti-neoplastic compound(s).

Thus, in a further aspect the invention relates to a compound of formula(I), (I*), (Ia) or (Ia*)—or a pharmaceutically acceptable saltthereof—for use as hereinbefore defined wherein said compound isadministered before, after or together with one or more otherpharmacologically active substance(s).

In a further aspect the invention relates to a compound of formula (I),(I*), (Ia) or (Ia*)—or a pharmaceutically acceptable salt thereof—foruse as hereinbefore defined, wherein said compound is administered incombination with one or more other pharmacologically activesubstance(s).

In a further aspect the invention relates to the use of a compound offormula (I), (I*), (Ia) or (Ia*)—or a pharmaceutically acceptable saltthereof—as hereinbefore defined wherein said compound is to beadministered before, after or together with one or more otherpharmacologically active substance(s).

In a further aspect the invention relates to a method (e.g. a method forthe treatment and/or prevention) as hereinbefore defined wherein thecompound of formula (I), (I*), (Ia) or (Ia*)—or a pharmaceuticallyacceptable salt thereof—is administered before, after or together with atherapeutically effective amount of one or more other pharmacologicallyactive substance(s).

In a further aspect the invention relates to a method (e.g. a method forthe treatment and/or prevention) as hereinbefore defined wherein thecompound of formula (I), (I*), (Ia) or (Ia*)—or a pharmaceuticallyacceptable salt thereof—is administered in combination with atherapeutically effective amount of one or more other pharmacologicallyactive substance(s).

In a further aspect the invention relates to a method for the treatmentand/or prevention of cancer comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of formula(I), (I*), (Ia) or (Ia*)—or a pharmaceutically acceptable saltthereof—and a therapeutically effective amount of one or more otherpharmacologically active substance(s), wherein the compound of formula(I), (I*), (Ia) or (Ia*)—or a pharmaceutically acceptable saltthereof—is administered simultaneously, concurrently, sequentially,successively, alternately or separately with the one or more otherpharmacologically active substance(s).

In a further aspect the invention relates to a method for the treatmentand/or prevention of cancer comprising administering to a patient inneed thereof a therapeutically effective amount of a RAS G12C inhibitor(preferably a KRAS G12C inhibitor)—or a pharmaceutically acceptable saltthereof—and a therapeutically effective amount of one or more otherpharmacologically active substance(s), wherein the RAS G12C inhibitor(preferably a KRAS G12C inhibitor)—or a pharmaceutically acceptable saltthereof—is administered in combination with the one or more otherpharmacologically active substance(s).

In a further aspect the invention relates to a compound of formula (I),(I*), (Ia) or (Ia*)—or a pharmaceutically acceptable salt thereof—foruse in the treatment and/or prevention of cancer, wherein the compoundof formula (I), (I*), (Ia) or (Ia*)—or a pharmaceutically acceptablesalt thereof—is administered simultaneously, concurrently, sequentially,successively, alternately or separately with the one or more otherpharmacologically active substance(s).

In a further aspect the invention relates to a RAS G12C inhibitor(preferably a KRAS G12C inhibitor)—or a pharmaceutically acceptable saltthereof—for use in the treatment and/or prevention of cancer, whereinthe RAS G12C inhibitor (preferably a KRAS G12C inhibitor)—or apharmaceutically acceptable salt thereof—is administered in combinationwith the one or more other pharmacologically active substance(s).

In a further aspect the invention relates to a kit comprising

-   -   a first pharmaceutical composition or dosage form comprising a        compound of formula (I), (I*), (Ia) or (Ia*)—or a        pharmaceutically acceptable salt thereof—and, optionally, one or        more pharmaceutically acceptable excipient(s), and    -   a second pharmaceutical composition or dosage form comprising        another pharmacologically active substance, and, optionally, one        or more pharmaceutically acceptable excipient(s),

for use in the treatment and/or prevention of cancer, wherein the firstpharmaceutical composition is to be administered simultaneously,concurrently, sequentially, successively, alternately or separately withthe second and/or additional pharmaceutical composition or dosage form.

In one aspect such kit for said use comprises a third pharmaceuticalcomposition or dosage form comprising a third pharmaceutical compositionor dosage form comprising still another pharmacologically activesubstance, and, optionally, one or more pharmaceutically acceptableexcipient(s)

In a further embodiment of the invention the components (i.e. thecombination partners) of the combinations, kits, uses, methods andcompounds for use according to the invention (including all embodiments)are administered simultaneously.

In a further embodiment of the invention the components (i.e. thecombination partners) of the combinations, kits, uses, methods andcompounds for use according to the invention (including all embodiments)are administered concurrently.

In a further embodiment of the invention the components (i.e. thecombination partners) of the combinations, kits, uses, methods andcompounds for use according to the invention (including all embodiments)are administered sequentially.

In a further embodiment of the invention the components (i.e. thecombination partners) of the combinations, kits, uses, methods andcompounds for use according to the invention (including all embodiments)are administered successively.

In a further embodiment of the invention the components (i.e. thecombination partners) of the combinations, kits, uses, methods andcompounds for use according to the invention (including all embodiments)are administered alternately.

In a further embodiment of the invention the components (i.e. thecombination partners) of the combinations, kits, uses, methods andcompounds for use according to the invention (including all embodiments)are administered separately.

The pharmacologically active substance(s) to be used together/incombination with the RAS G12C inhibitor (preferably a KRAS G12Cinhibitor) and/or to be used together/in combination with the compoundof formula (I), (I*), (Ia) or (Ia*)—or a pharmaceutically acceptablesalt thereof—(including all individual embodiments or generic subsets ofcompounds (I), (I*), (Ia) or (Ia*)) or in the medical uses, uses,methods of treatment and/or prevention as herein (above and below)defined can be selected from any one or more of the following(preferably there is one or two additional pharmacologically activesubstance used in all these embodiments):

1. an inhibitor of EGFR and/or ErbB2 (HER2) and/or ErbB3 (HER3) and/orErbB4 (HER4) or of any mutants thereof

-   -   a. irreversible inhibitors: e.g. afatinib, dacomitinib,        canertinib, neratinib, avitinib, poziotinib, AV 412, PF-6274484,        HKI 357, olmutinib, osimertinib, almonertinib, nazartinib,        lazertinib, pelitinib;    -   b. reversible inhibitors: e.g. erlotinib, gefitinib, icotinib,        sapitinib, lapatinib, varlitinib, vandetanib, TAK-285, AEE788,        BMS599626/AC-480, GW 583340;    -   c. anti-EGFR antibodies: e.g. necitumumab, panitumumab,        cetuximab, amivantamab;    -   d. anti-HER2 antibodies: e.g. pertuzumab, trastuzumab,        trastuzumab emtansine;    -   e. inhibitors of mutant EGFR;    -   f. an inhibitor of HER2 with exon 20 mutations;    -   g. preferred irreversible inhibitor is afatinib;    -   h. preferred anti-EGFR antibody is cetuximab.

2. an inhibitor of MEK and/or of mutants thereof

-   -   a. e.g. trametinib, cobimetinib, binimetinib, selumetinib,        refametinib, BI 3011441;    -   b. preferred are trametinib and BI 3011441;    -   c. most preferred is BI 3011441;    -   d. a MEK inhibitor as disclosed in WO 2013/136249;    -   e. a MEK inhibitor as disclosed in WO 2013/136254

3. an inhibitor of SOS1 and/or of any mutants thereof (i.e. a compoundthat modulates/inhibits the GEF functionality of SOS1, e.g. by bindingto SOS1 and preventing protein-protein interaction between SOS1 and a(mutant) Ras protein, e.g. KRAS)

-   -   a. e.g. BAY-293, BI-3406, BI 1701963;    -   b. preferred are BI-3406 and BI 1701963;    -   c. most preferred is BI 1701963;    -   d. a SOS1 inhibitor as disclosed in WO 2018/115380;    -   e. a SOS1 inhibitor as disclosed in WO 2019/122129;    -   f. a SOS1 inhibitor as disclosed in WO 2020/180768, WO        2020/180770, WO 2018/172250 and WO 2019/201848.

4. an oncolytic virus

5. a RAS vaccine

-   -   a. e.g. TGO2 (Targovax).

6. a cell cycle inhibitor

-   -   a. e.g. inhibitors of CDK4/6 and/or of any mutants thereof        -   i. e.g. palbociclib, ribociclib, abemaciclib, trilaciclib,            PF-06873600;        -   ii. preferred are palbociclib and abemaciclib;        -   iii. most preferred is abemaciclib.    -   b. e.g. vinca alkaloids        -   i. e.g. vinorelbine.    -   c. e.g. inhibitors of Aurora kinase and/or of any mutants        thereof        -   i. e.g. alisertib, barasertib.

7. an inhibitor of PTK2 (=FAK) and/or of any mutants thereof

-   -   a. e.g. TAE226, BI 853520.

8. an inhibitor of SHP2 and/or of any mutants thereof

-   -   a. e.g. SHP099, TNO155, RMC-4550, RMC-4630, IACS-13909.

9. an inhibitor of PI3 kinase (=PI3K) and/or of any mutants thereof

-   -   a. e.g. inhibitors of PI3Kα and/or of any mutants thereof        -   i. e.g. alpelisib, serabelisib, GDC-0077, HH-CYH33, AMG 511,            buparlisib, dactolisib, pictilisib, taselisib.

10. an inhibitor of FGFR1 and/or FGFR2 and/or FGFR3 and/or of anymutants thereof

-   -   a. e.g. ponatinib, infigratinib, nintedanib.

11. an inhibitor of AXL and/or of any mutants thereof

12. a taxane

-   -   a. e.g. paclitaxel, nab-paclitaxel, docetaxel;    -   b. preferred is paclitaxel.

13. a platinum-containing compound

-   -   a. e.g. cisplatin, carboplatin, oxaliplatin    -   b. preferred is oxaliplatin.

14. an anti-metabolite

-   -   a. e.g. 5-fluorouracil, capecitabine, floxuridine, cytarabine,        gemcitabine, pemetrexed, combination of trifluridine and        tipiracil (=TAS102);    -   b. preferred is 5-fluorouracil.

15. an immunotherapeutic agent

-   -   a. e.g. an immune checkpoint inhibitor        -   i. e.g. an anti-CTLA4 mAb, anti-PD1 mAb, anti-PD-L1 mAb,            anti-PD-L2 mAb, anti-LAG3 mAb, anti-TIM3 mAb;        -   ii. preferred is an anti-PD1 mAb;        -   iii. e.g. ipilimumab, nivolumab, pembrolizumab, tislelizumab            atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001            (=spartalizumab), AMG-404, ezabenlimab;        -   iv. preferred are nivolumab, pembrolizumab, ezabenlimab and            PDR-001 (=spartalizumab);        -   v. most preferred is ezabenlimab, pembrolizumab and            nivolumab.

16. a topoisomerase inhibitor

-   -   a. e.g. irinotecan, liposomal irinotecan (nal-IRI), topotecan,        etoposide;    -   b. most preferred is irinotecan and liposomal irinotecan        (nal-IRI).

17. an inhibitor of A-Raf and/or B-Raf and/or C-Raf and/or of anymutants thereof

-   -   a. e.g. encorafenib, dabrafenib, vemurafenib, PLX-8394, RAF-709        (=example 131 in WO 2014/151616), LXH254, sorafenib, LY-3009120        (=example 1 in WO 2013/134243), lifirafenib, TAK-632,        agerafenib, CCT196969, RO5126766, RAF265.

18. an inhibitor of mTOR

-   -   a. e.g. rapamycin, temsirolimus, everolimus, ridaforolimus,        zotarolimus, sapanisertib, Torin 1, dactolisib, GDC-0349,        VS-5584, vistusertib, AZD8055.

19. an epigenetic regulator

-   -   a. e.g. a BET inhibitor        -   i. e.g. JQ-1, GSK 525762, OTX-015, CPI-0610, TEN—010,            OTX-015, PLX51107, ABBV-075, ABBV-744, BMS986158, TGI-1601,            CC-90010, AZD5153, 1-BET151, BI 894999;        -   ii. preferred is BI 894999.

20. an inhibitor of IGF1/2 and/or of IGF1-R and/or of any mutantsthereof

-   -   a. e.g. xentuzumab (antibody 60833 in WO 2010/066868), MEDI-573        (=dusigitumab), linsitinib.

21. an inhibitor of a Src family kinase and/or of any mutants thereof

-   -   a. e.g. an inhibitor of a kinase of the SrcA subfamily and/or of        any mutants thereof, i.e. an inhibitor of Src, Yes, Fyn, Fgr        and/or of any mutants thereof;    -   b. e.g. an inhibitor of a kinase of the SrcB subfamily and/or of        any mutants thereof, i.e. an inhibitor of Lck, Hck, Blk, Lyn        and/or of any mutants thereof;    -   c. e.g. an inhibitor of a kinase of the Frk subfamily and/or of        any mutants thereof, i.e. an inhibitor of Frk and/or of any        mutants thereof;    -   d. e.g. dasatinib, ponatinib, bosutinib, vandetanib, KX-01,        saracatinib, KX2-391, SU 6656, WH-4-023.

22. an apoptose regulator

-   -   a. e.g. an MDM2 inhibitor, e.g. an inhibitor of the interaction        between p53 (preferably functional p53, most preferably wt p53)        and MDM2 and/or of any mutants thereof;        -   i. e.g. HDM-201, NVP-CGM097, RG-7112, MK-8242, RG-7388,            SAR405838, AMG-232, DS-3032, RG-7775, APG-115, BI 907828;        -   ii. preferred are HDM-201, RG-7388, AMG-232 and BI 907828;        -   iii. most preferred is BI 907828;        -   iv. an MDM2 inhibitor as disclosed in WO 2015/155332;        -   v. an MDM2 inhibitor as disclosed in WO 2016/001376;        -   vi. an MDM2 inhibitor as disclosed in WO 2016/026937;        -   vii. an MDM2 inhibitor as disclosed in WO 2017/060431;    -   b. e.g. a PARP inhibitor;    -   c. e.g. an MCL-1 inhibitor;        -   i. e.g. AZD-5991, AMG-176, AMG-397, S64315, S63845,            A-1210477;

23. an inhibitor of c-MET and/or of any mutants thereof

-   -   a. e.g. savolitinib, cabozantinib, foretinib;    -   b. MET antibodies, e.g. emibetuzumab, amivantamab;

24. an inhibitor of ERK and/or of any mutants thereof

-   -   a. e.g. ulixertinib, LTT462;

25. an inhibitor of farnesyl transferase and/or of any mutants thereof

-   -   a. e.g. tipifarnib;

In a further embodiment of the (combined) use and method (e.g. methodfor the treatment and/or prevention) as hereinbefore described one otherpharmacologically active substance is to be administered before, afteror together with the compound of formula (I), (I*), (Ia) or (Ia*)—or apharmaceutically acceptable salt thereof—wherein said one otherpharmacologically active substance is

-   -   a SOS1 inhibitor; or    -   BI 1701963; or    -   a MEK inhibitor; or    -   trametinib, or    -   BI 3011441; or    -   an anti-PD-1 antibody; or    -   ezabenlimab; or    -   cetuximab; or    -   afatinib; or    -   standard of care (SoC) in a given indication; or    -   a PI3 kinase inhibitor.

In a further embodiment of the (combined) use and method (e.g. methodfor the treatment and/or prevention) as hereinbefore described one otherpharmacologically active substance is to be administered in combinationwith the compound of formula (I), (I*), (Ia) or (Ia*)—or apharmaceutically acceptable salt thereof—wherein said one otherpharmacologically active substance is

-   -   a SOS1 inhibitor; or    -   BI 1701963; or    -   a MEK inhibitor; or    -   trametinib; or    -   BI 3011441; or    -   an anti-PD-1 antibody; or    -   ezabenlimab; or    -   cetuximab; or    -   afatinib; or    -   standard of care (SoC) in a given indication; or    -   a PI3 kinase inhibitor.

In a further aspect of the (combined) use and method (e.g. method forthe treatment and/or prevention) as hereinbefore described two otherpharmacologically active substances are to be administered before, afteror together with the compound of formula (I), (I*), (Ia) or (Ia*)—or apharmaceutically acceptable salt thereof—wherein said two otherpharmacologically active substances are

-   -   a MEK inhibitor (preferably BI 3011441) and a SOS1 inhibitor        (preferably BI 1701963); or    -   trametinib and a SOS1 inhibitor (preferably BI 1701963); or    -   an anti-PD-1 antibody (preferably ezabenlimab) and an anti-LAG-3        antibody; or    -   an anti-PD-1 antibody (preferably ezabenlimab) and a SOS1        inhibitor (preferably BI 1701963); or    -   a MEK inhibitor (preferably BI 3011441) and an inhibitor        selected from the group consisting of an EGFR inhibitor and/or        ErbB2 (HER2) inhibitor and/or inhibitor of any mutants thereof;        or    -   a SOS1 inhibitor (preferably BI 1701963) and an inhibitor        selected from the group consisting of an EGFR inhibitor and/or        ErbB2 (HER2) inhibitor and/or inhibitor of any mutants thereof;        or    -   a MEK inhibitor (preferably BI 3011441) and afatinib; or    -   a MEK inhibitor (preferably BI 3011441) and cetuximab; or    -   trametinib and afatinib; or    -   trametinib and cetuximab; or    -   a SOS1 inhibitor (preferably BI 1701963) and afatinib; or    -   a SOS1 inhibitor (preferably BI 1701963) and cetuximab.

In a further aspect of the (combined) use and method (e.g. method forthe treatment and/or prevention) as hereinbefore described two otherpharmacologically active substances are to be administered incombination with the compound of formula (I), (I*), (Ia) or (Ia*)—or apharmaceutically acceptable salt thereof—wherein said two otherpharmacologically active substances are

-   -   a MEK inhibitor (preferably BI 3011441) and a SOS1 inhibitor        (preferably BI 1701963); or    -   trametinib and a SOS1 inhibitor (preferably BI 1701963); or    -   an anti-PD-1 antibody (preferably ezabenlimab) and an anti-LAG-3        antibody; or    -   an anti-PD-1 antibody (preferably ezabenlimab) and a SOS1        inhibitor (preferably BI 1701963); or    -   a MEK inhibitor (preferably BI 3011441) and an inhibitor        selected from the group consisting of an EGFR inhibitor and/or        ErbB2 (HER2) inhibitor and/or inhibitor of any mutants thereof;        or    -   a SOS1 inhibitor (preferably BI 1701963) and an inhibitor        selected from the group consisting of an EGFR inhibitor and/or        ErbB2 (HER2) inhibitor and/or inhibitor of any mutants thereof;        or    -   a MEK inhibitor (preferably BI 3011441) and afatinib; or    -   a MEK inhibitor (preferably BI 3011441) and cetuximab; or    -   trametinib and afatinib; or    -   trametinib and cetuximab; or    -   a SOS1 inhibitor (preferably BI 1701963) and afatinib; or    -   a SOS1 inhibitor (preferably BI 1701963) and cetuximab.

Additional pharmacologically active substance(s) which can also be usedtogether/in combination with the compound of formula (I), (I*), (Ia) or(Ia*)—or a pharmaceutically acceptable salt thereof—(including allindividual embodiments or generic subsets of compounds (I), (I*), (Ia)or (Ia*)) or in the medical uses, uses, methods of treatment and/orprevention as herein (above and below) defined include, without beingrestricted thereto, hormones, hormone analogues and antihormones (e.g.tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate,flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproteroneacetate, finasteride, buserelin acetate, fludrocortisone,fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors(e.g. anastrozole, letrozole, liarozole, vorozole, exemestane,atamestane), LHRH agonists and antagonists (e.g. goserelin acetate,luprolide), inhibitors of growth factors and/or of their correspondingreceptors (growth factors such as for example platelet derived growthfactor (PDGF), fibroblast growth factor (FGF), vascular endothelialgrowth factor (VEGF), epidermal growth factor (EGF), insuline-likegrowth factors (IGF), human epidermal growth factor (HER, e.g. HER2,HER3, HER4) and hepatocyte growth factor (HGF) and/or theircorresponding receptors), inhibitors are for example (anti-)growthfactor antibodies, (anti-)growth factor receptor antibodies and tyrosinekinase inhibitors, such as for example cetuximab, gefitinib, afatinib,nintedanib, imatinib, lapatinib, bosutinib, bevacizumab andtrastuzumab); antimetabolites (e.g. antifolates such as methotrexate,raltitrexed, pyrimidine analogues such as 5-fluorouracil (5-FU),ribonucleoside and deoxyribonucleoside analogues, capecitabine andgemcitabine, purine and adenosine analogues such as mercaptopurine,thioguanine, cladribine and pentostatin, cytarabine (ara C),fludarabine); antitumor antibiotics (e.g. anthracyclins such asdoxorubicin, doxil (pegylated liposomal doxorubicin hydrochloride,myocet (non-pegylated liposomal doxorubicin), daunorubicin, epirubicinand idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin,streptozocin); platinum derivatives (e.g. cisplatin, oxaliplatin,carboplatin); alkylation agents (e.g. estramustin, meclorethamine,melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide,ifosfamide, temozolomide, nitrosoureas such as for example carmustin andlomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such asfor example vinblastine, vindesin, vinorelbin and vincristine; andtaxanes such as paclitaxel, docetaxel); angiogenesis inhibitors (e.g.tasquinimod), tubuline inhibitors; DNA synthesis inhibitors, PARPinhibitors, topoisomerase inhibitors (e.g. epipodophyllotoxins such asfor example etoposide and etopophos, teniposide, amsacrin, topotecan,irinotecan, mitoxantrone), serine/threonine kinase inhibitors (e.g. PDK1 inhibitors, Raf inhibitors, A-Raf inhibitors, B-Raf inhibitors, C-Rafinhibitors, mTOR inhibitors, mTORC1/2 inhibitors, PI3K inhibitors, PI3Kαinhibitors, dual mTOR/PI3K inhibitors, STK 33 inhibitors, AKTinhibitors, PLK 1 inhibitors, inhibitors of CDKs, Aurora kinaseinhibitors), tyrosine kinase inhibitors (e.g. PTK2/FAK inhibitors),protein protein interaction inhibitors (e.g. IAP inhibitors/SMACmimetics, Mcl-1, MDM2/MDMX), MEK inhibitors, ERK inhibitors, FLT3inhibitors, BRD4 inhibitors, IGF-1R inhibitors, TRAILR2 agonists, Bcl-xLinhibitors, Bcl-2 inhibitors (e.g. venetoclax), Bcl-2/Bcl-xL inhibitors,ErbB receptor inhibitors, BCR-ABL inhibitors, ABL inhibitors, Srcinhibitors, rapamycin analogs (e.g. everolimus, temsirolimus,ridaforolimus, sirolimus), androgen synthesis inhibitors, androgenreceptor inhibitors, DNMT inhibitors, HDAC inhibitors, ANG1/2inhibitors, CYP17 inhibitors, radiopharmaceuticals, proteasomeinhibitors (e.g. carfilzomib), immunotherapeutic agents such as immunecheckpont inhibitors (e.g. CTLA4, PD1, PD-L1, PD-L2, LAG3, and TIM3binding molecules/immunoglobulins, such as e.g. ipilimumab, nivolumab,pembrolizumab), ADCC (antibody-dependent cell-mediated cytotoxicity)enhancers (e.g. anti-CD33 antibodies, anti-CD37 antibodies, anti-CD20antibodies), t-cell engagers (e.g. bi-specific T-cell engagers (BiTEs®)like e.g. CD3×BCMA, CD3×CD33, CD3×CD19), PSMA×CD3), tumor vaccines andvarious chemotherapeutic agents such as amifostin, anagrelid, clodronat,filgrastin, interferon, interferon alpha, leucovorin, procarbazine,levamisole, mesna, mitotane, pamidronate and porfimer.

It is to be understood that the combinations, compositions, kits,methods, uses or compounds for use according to this invention mayenvisage the simultaneous, concurrent, sequential, successive, alternateor separate administration of the active ingredients or components. Itwill be appreciated that the compound of formula (I), (I*), (Ia) or(Ia*)—or a pharmaceutically acceptable salt thereof—and the one or moreother pharmacologically active substance(s) can be administeredformulated either dependently or independently, such as e.g. thecompound of formula (I), (I*), (Ia) or (Ia*)—or a pharmaceuticallyacceptable salt thereof—and the one or more other pharmacologicallyactive substance(s) may be administered either as part of the samepharmaceutical composition/dosage form or, preferably, in separatepharmaceutical compositions/dosage forms.

In this context, “combination” or “combined” within the meaning of thisinvention includes, without being limited, a product that results fromthe mixing or combining of more than one active ingredient and includesboth fixed and non-fixed (e.g. free) combinations (including kits) anduses, such as e.g. the simultaneous, concurrent, sequential, successive,alternate or separate use of the components or ingredients. The term“fixed combination” means that the active ingredients are administeredto a patient simultaneously in the form of a single entity or dosage.The term “non-fixed combination” means that the active ingredients areadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific time limits, wherein suchadministration provides therapeutically effective levels of thecompounds in the body of the patient.

The administration of the compound of formula (I), (I*), (Ia) or(Ia*)—or a pharmaceutically acceptable salt thereof—and the one or moreother pharmacologically active substance(s) may take place byco-administering the active components or ingredients, such as e.g. byadministering them simultaneously or concurrently in one single or intwo or more separate formulations or dosage forms. Alternatively, theadministration of the compound of formula (I), (I*), (Ia) or (Ia*)—or apharmaceutically acceptable salt thereof—and the one or more otherpharmacologically active substance(s) may take place by administeringthe active components or ingredients sequentially or in alternation,such as e.g. in two or more separate formulations or dosage forms.

For example, simultaneous administration includes administration atsubstantially the same time. This form of administration may also bereferred to as “concomitant” administration. Concurrent administrationincludes administering the active agents within the same general timeperiod, for example on the same day(s) but not necessarily at the sametime. Alternate administration includes administration of one agentduring a time period, for example over the course of a few days or aweek, followed by administration of the other agent(s) during asubsequent period of time, for example over the course of a few days ora week, and then repeating the pattern for one or more cycles.Sequential or successive administration includes administration of oneagent during a first time period (for example over the course of a fewdays or a week) using one or more doses, followed by administration ofthe other agent(s) during a second and/or additional time period (forexample over the course of a few days or a week) using one or moredoses. An overlapping schedule may also be employed, which includesadministration of the active agents on different days over the treatmentperiod, not necessarily according to a regular sequence. Variations onthese general guidelines may also be employed, e.g. according to theagents used and the condition of the subject.

Definitions

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to:

The use of the prefix C_(x-y), wherein x and y each represent a positiveinteger (x<y), indicates that the chain or ring structure or combinationof chain and ring structure as a whole, specified and mentioned indirect association, may consist of a maximum of y and a minimum of xcarbon atoms.

The indication of the number of members in groups that contain one ormore heteroatom(s) (e.g. heteroaryl, heteroarylalkyl, heterocyclyl,heterocycylalkyl) relates to the total number of atoms of all the ringmembers or the total of all the ring and carbon chain members.

The indication of the number of carbon atoms in groups that consist of acombination of carbon chain and carbon ring structure (e.g.cycloalkylalkyl, arylalkyl) relates to the total number of carbon atomsof all the carbon ring and carbon chain members. Obviously, a ringstructure has at least three members.

In general, for groups comprising two or more subgroups (e.g.heteroarylalkyl, heterocycylalkyl, cycloalkylalkyl, arylalkyl) the lastnamed subgroup is the radical attachment point, for example, thesubstituent aryl-C₁₋₆alkyl means an aryl group which is bound to aC₁₋₆alkyl group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

In groups like HO, H₂N, (O)S, (O)₂S, NC (cyano), HOOC, F₃C or the like,the skilled artisan can see the radical attachment point(s) to themolecule from the free valences of the group itself.

Alkyl denotes monovalent, saturated hydrocarbon chains, which may bepresent in both straight-chain (unbranched) and branched form. If analkyl is substituted, the substitution may take place independently ofone another, by mono- or polysubstitution in each case, on all thehydrogen-carrying carbon atoms.

The term “C₁₋₅alkyl” includes for example H₃C—, H₃C—CH₂—, H₃C—CH₂—CH₂—,H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—, H₃C—CH(CH₃)—CH₂—,H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—, H₃C—CH₂—CH₂—CH(CH₃)—,H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—, H₃C—CH₂—C(CH₃)₂—,H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— and H₃C—CH₂—CH(CH₂CH₃)—.

Further examples of alkyl are methyl (Me; —CH₃), ethyl (Et; —CH₂CH₃),1-propyl (n-propyl; n-Pr; —CH₂CH₂CH₃), 2-propyl (i-Pr; iso-propyl;—CH(CH₃)₂), 1-butyl (n-butyl; n-Bu; —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl(iso-butyl; i-Bu; —CH₂CH(CH₃)₂), 2-butyl (sec-butyl; sec-Bu;—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (tert-butyl; t-Bu; —C(CH₃)₃),1-pentyl (n-pentyl; —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃),3-pentyl (—CH(CH₂CH₃)₂), 3-methyl-1-butyl (iso-pentyl; —CH₂CH₂CH(CH₃)₂),2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂),2,2-dimethyl-1-propyl (neo-pentyl; —CH₂C(CH₃)₃), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (n-hexyl; —CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃), 2,3-dimethyl-1-butyl(—CH₂CH(CH₃)CH(CH₃)CH₃), 2,2-dimethyl-1-butyl (—CH₂C(CH₃)₂CH₂CH₃),3,3-dimethyl-1-butyl (—CH₂CH₂C(CH₃)₃), 2-methyl-1-pentyl(—CH₂CH(CH₃)CH₂CH₂CH₃), 3-methyl-1-pentyl (—CH₂CH₂CH(CH₃)CH₂CH₃),1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl,2,2-dimethyl-1-pentyl, 2,3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl,3,3-dimethyl-1-pentyl, 2,2,3-trimethyl-1-butyl, 3-ethyl-1-pentyl,1-octyl (n-octyl), 1-nonyl (n-nonyl); 1-decyl (n-decyl) etc.

By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyletc. without any further definition are meant saturated hydrocarbongroups with the corresponding number of carbon atoms, wherein allisomeric forms are included.

The above definition for alkyl also applies if alkyl is a part ofanother (combined) group such as for example C_(x-y)alkylamino orC_(x-y)alkyloxy.

The term alkylene can also be derived from alkyl. Alkylene is bivalent,unlike alkyl, and requires two binding partners. Formally, the secondvalency is produced by removing a hydrogen atom in an alkyl.Corresponding groups are for example—CH₃ and —CH₂—, —CH₂CH₃ and —CH₂CH₂—or >CHCH₃ etc.

The term “C₁₋₄alkylene” includes for example—(CH₂)—, —(CH₂—CH₂)—,—(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—,—(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—,—(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—,—(CH₂—C(CH₃)₂)—, —(C(CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—,—(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—,—(CH(CH(CH₃))₂)—and —C(CH₃)(CH₂CH₃)—.

Other examples of alkylene are methylene, ethylene, propylene,1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene,1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene,2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene,hexylene etc.

By the generic terms propylene, butylene, pentylene, hexylene etc.without any further definition are meant all the conceivable isomericforms with the corresponding number of carbon atoms, i.e. propyleneincludes 1-methylethylene and butylene includes 1-methylpropylene,2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.

The above definition for alkylene also applies if alkylene is part ofanother (combined) group such as for example in HO-C_(x-y)alkyleneaminoor H₂N-C_(x-y)alkyleneoxy.

Unlike alkyl, alkenyl consists of at least two carbon atoms, wherein atleast two adjacent carbon atoms are joined together by a C—C double bondand a carbon atom can only be part of one C—C double bond. If in analkyl as hereinbefore defined having at least two carbon atoms, twohydrogen atoms on adjacent carbon atoms are formally removed and thefree valencies are saturated to form a second bond, the correspondingalkenyl is formed.

Examples of alkenyl are vinyl (ethenyl), prop-1-enyl, allyl(prop-2-enyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl,2-methyl-prop-2-enyl, 2-methyl-prop-1-enyl, 1-methyl-prop-2-enyl,1-methyl-prop-1-enyl, 1-methylidenepropyl, pent-1-enyl, pent-2-enyl,pent-3-enyl, pent-4-enyl, 3-methyl-but-3-enyl, 3-methyl-but-2-enyl,3-methyl-but-1-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl,hex-5-enyl, 2,3-dimethyl-but-3-enyl, 2,3-dimethyl-but-2-enyl,2-methylidene-3-methylbutyl, 2,3-dimethyl-but-1-enyl, hexa-1,3-dienyl,hexa-1,4-dienyl, penta-1,4-dienyl, penta-1,3-dienyl, buta-1,3-dienyl,2,3-dimethylbuta-1,3-diene etc.

By the generic terms propenyl, butenyl, pentenyl, hexenyl, butadienyl,pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyletc. without any further definition are meant all the conceivableisomeric forms with the corresponding number of carbon atoms, i.e.propenyl includes prop-1-enyl and prop-2-enyl, butenyl includesbut-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl,1-methyl-prop-2-enyl etc.

Alkenyl may optionally be present in the cis or trans or E or Zorientation with regard to the double bond(s).

The above definition for alkenyl also applies when alkenyl is part ofanother (combined) group such as for example in C_(x-y)alkenylamino orC_(x-y)alkenyloxy.

Unlike alkylene, alkenylene consists of at least two carbon atoms,wherein at least two adjacent carbon atoms are joined together by a C—Cdouble bond and a carbon atom can only be part of one C—C double bond.If in an alkylene as hereinbefore defined having at least two carbonatoms, two hydrogen atoms at adjacent carbon atoms are formally removedand the free valencies are saturated to form a second bond, thecorresponding alkenylene is formed.

Examples of alkenylene are ethenylene, propenylene, 1-methylethenylene,butenylene, 1-methylpropenylene, 1,1-dimethylethenylene,1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene,2,2-dimethylpropenylene, 1,2-dimethylpropenylene,1,3-dimethylpropenylene, hexenylene etc.

By the generic terms propenylene, butenylene, pentenylene, hexenyleneetc. without any further definition are meant all the conceivableisomeric forms with the corresponding number of carbon atoms, i.e.propenylene includes 1-methylethenylene and butenylene includes1-methylpropenylene, 2-methylpropenylene, 1,1-dimethylethenylene and1,2-dimethylethenylene.

Alkenylene may optionally be present in the cis or trans or E or Zorientation with regard to the double bond(s).

The above definition for alkenylene also applies when alkenylene is apart of another (combined) group as for example inHO—C_(x-y)alkenyleneamino or H₂N—C_(x-y)alkenyleneoxy.

Unlike alkyl, alkynyl consists of at least two carbon atoms, wherein atleast two adjacent carbon atoms are joined together by a C—C triplebond. If in an alkyl as hereinbefore defined having at least two carbonatoms, two hydrogen atoms in each case at adjacent carbon atoms areformally removed and the free valencies are saturated to form twofurther bonds, the corresponding alkynyl is formed.

Examples of alkynyl are ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl,but-2-ynyl, but-3-ynyl, 1-methyl-prop-2-ynyl, pent-1-ynyl, pent-2-ynyl,pent-3-ynyl, pent-4-ynyl, 3-methyl-but-1-ynyl, hex-1-ynyl, hex-2-ynyl,hex-3-ynyl, hex-4-ynyl, hex-5-ynyl etc.

By the generic terms propynyl, butynyl, pentynyl, hexynyl, heptynyl,octynyl, nonynyl, decynyl etc. without any further definition are meantall the conceivable isomeric forms with the corresponding number ofcarbon atoms, i.e. propynyl includes prop-1-ynyl and prop-2-ynyl,butynyl includes but-1-ynyl, but-2-ynyl, but-3-ynyl,1-methyl-prop-1-ynyl, 1-methyl-prop-2-ynyl, etc.

If a hydrocarbon chain carries both at least one double bond and also atleast one triple bond, by definition it belongs to the alkynyl subgroup.

The above definition for alkynyl also applies if alkynyl is part ofanother (combined) group, as for example in C_(x-y)alkynylamino orC_(x-y)alkynyloxy.

Unlike alkylene, alkynylene consists of at least two carbon atoms,wherein at least two adjacent carbon atoms are joined together by a C—Ctriple bond. If in an alkylene as hereinbefore defined having at leasttwo carbon atoms, two hydrogen atoms in each case at adjacent carbonatoms are formally removed and the free valencies are saturated to formtwo further bonds, the corresponding alkynylene is formed.

Examples of alkynylene are ethynylene, propynylene, 1-methylethynylene,butynylene, 1-methylpropynylene, 1,1-dimethylethynylene,1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene,2,2-dimethylpropynylene, 1,2-dimethylpropynylene,1,3-dimethylpropynylene, hexynylene etc.

By the generic terms propynylene, butynylene, pentynylene, hexynyleneetc. without any further definition are meant all the conceivableisomeric forms with the corresponding number of carbon atoms, i.e.propynylene includes 1-methylethynylene and butynylene includes1-methylpropynylene, 2-methylpropynylene, 1,1-dimethylethynylene and1,2-dimethylethynylene.

The above definition for alkynylene also applies if alkynylene is partof another (combined) group, as for example in HO-C_(x-y)alkynyleneaminoor H₂N-C_(x-y)alkynyleneoxy.

By heteroatoms are meant oxygen, nitrogen and sulphur atoms.

Haloalkyl (haloalkenyl, haloalkynyl) is derived from the previouslydefined alkyl (alkenyl, alkynyl) by replacing one or more hydrogen atomsof the hydrocarbon chain independently of one another by halogen atoms,which may be identical or different. If a haloalkyl (haloalkenyl,haloalkynyl) is to be further substituted, the substitutions may takeplace independently of one another, in the form of mono- orpolysubstitutions in each case, on all the hydrogen-carrying carbonatoms.

Examples of haloalkyl (haloalkenyl, haloalkynyl) are —CF₃, —CHF₂, —CH₂F,—CF₂CF₃, —CHFCF₃, —CH₂CF₃, —CF₂CH₃, —CHFCH₃, —CF₂CF₂CF₃, —CF₂CH₂CH₃,—CF═CF₂, —CCI═CH₂, —CBr═CH₂, —C═C—CF₃, —CHFCH₂CH₃, —CHFCH₂CF₃ etc.

From the previously defined haloalkyl (haloalkenyl, haloalkynyl) arealso derived the terms haloalkylene (haloalkenylene, haloalkynylene).Haloalkylene (haloalkenylene, haloalkynylene), unlike haloalkyl(haloalkenyl, haloalkynyl), is bivalent and requires two bindingpartners. Formally, the second valency is formed by removing a hydrogenatom from a haloalkyl (haloalkenyl, haloalkynyl).

Corresponding groups are for example—CH₂F and —CHF—, —CHFCH₂F and—CHFCHF— or >CFCH₂F etc.

The above definitions also apply if the corresponding halogen-containinggroups are part of another (combined) group.

Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.

Cycloalkyl is made up of the subgroups monocyclic cycloalkyl, bicycliccycloalkyl and spiro-cycloalkyl. The ring systems are saturated andformed by linked carbon atoms. In bicyclic cycloalkyl two rings arejoined together so that they have at least two carbon atoms in common.In spiro-cycloalkyl one carbon atom (spiroatom) belongs to two ringstogether.

If a cycloalkyl is to be substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon atoms. Cycloalkylitself may be linked as a substituent to the molecule via every suitableposition of the ring system.

Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, bicyclo[2.2.0]hexyl, bicyclo[3.2.0]heptyl,bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[4.3.0]nonyl(octahydroindenyl), bicyclo[4.4.0]decyl (decahydronaphthyl),bicyclo[2.2.1]heptyl (norbornyl), bicyclo[4.1.0]heptyl (norcaranyl),bicyclo[3.1.1]heptyl (pinanyl), spiro[2.5]octyl, spiro[3.3]heptyl etc.

The above definition for cycloalkyl also applies if cycloalkyl is partof another (combined) group as for example in C_(x-y)cycloalkylamino,C_(x-y)cycloalkyloxy or C_(x-y)cycloalkylalkyl.

If the free valency of a cycloalkyl is saturated, then an alicycle isobtained.

The term cycloalkylene can thus be derived from the previously definedcycloalkyl.

Cycloalkylene, unlike cycloalkyl, is bivalent and requires two bindingpartners. Formally, the second valency is obtained by removing ahydrogen atom from a cycloalkyl.

Corresponding groups are for example:

-   -   cyclohexyl and

(cyclohexylene).

The above definition for cycloalkylene also applies if cycloalkylene ispart of another (combined) group as for example inHO-C_(x-y)cycloalkyleneamino or H₂N-C_(x-y)cycloalkyleneoxy.

Cycloalkenyl is made up of the subgroups monocyclic cycloalkenyl,bicyclic cycloalkeny and spiro-cycloalkenyl. However, the systems areunsaturated, i.e. there is at least one C—C double bond but no aromaticsystem. If in a cycloalkyl as hereinbefore defined two hydrogen atoms atadjacent cyclic carbon atoms are formally removed and the free valenciesare saturated to form a second bond, the corresponding cycloalkenyl isobtained.

If a cycloalkenyl is to be substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon atoms. Cycloalkenylitself may be linked as a substituent to the molecule via every suitableposition of the ring system.

Examples of cycloalkenyl are cycloprop-1-enyl, cycloprop-2-enyl,cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl,cyclopent-3-enyl, cyclohex-1-enyl, cyclohex-2-enyl, cyclohex-3-enyl,cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl, cyclohept-4-enyl,cyclobuta-1,3-dienyl, cyclopenta-1,4-dienyl, cyclopenta-1,3-dienyl,cyclopenta-2,4-dienyl, cyclohexa-1,3-dienyl, cyclohexa-1,5-dienyl,cyclohexa-2,4-dienyl, cyclohexa-1,4-dienyl, cyclohexa-2,5-dienyl,bicyclo[2.2.1]hepta-2,5-dienyl (norborna-2,5-dienyl),bicyclo[2.2.1]hept-2-enyl (norbornenyl), spiro[4,5]dec-2-enyl etc.

The above definition for cycloalkenyl also applies when cycloalkenyl ispart of another (combined) group as for example inC_(x-y)cycloalkenylamino, C_(x-y)cycloalkenyloxy orC_(x-y)cycloalkenylalkyl.

If the free valency of a cycloalkenyl is saturated, then an unsaturatedalicycle is obtained.

The term cycloalkenylene can thus be derived from the previously definedcycloalkenyl. Cycloalkenylene, unlike cycloalkenyl, is bivalent andrequires two binding partners. Formally, the second valency is obtainedby removing a hydrogen atom from a cycloalkenyl. Corresponding groupsare for example:

cyclopentenyl and

(cyclopentenylene) etc.

The above definition for cycloalkenylene also applies if cycloalkenyleneis part of another (combined) group as for example inHO-C_(x-y)cycloalkenyleneamino or H₂N—C_(x-y)cycloalkenyleneoxy.

Aryl denotes mono-, bi- or tricyclic carbocycles with at least onearomatic carbocycle. Preferably, it denotes a monocyclic group with sixcarbon atoms (phenyl) or a bicyclic group with nine or ten carbon atoms(two six-membered rings or one six-membered ring with a five-memberedring), wherein the second ring may also be aromatic or, however, mayalso be partially saturated.

If an aryl is to be substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon atoms. Aryl itself maybe linked as a substituent to the molecule via every suitable positionof the ring system.

Examples of aryl are phenyl, naphthyl, indanyl (2,3-dihydroindenyl),indenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl(1,2,3,4-tetrahydronaphthyl, tetralinyl), dihydronaphthyl(1,2-dihydronaphthyl), fluorenyl etc. Most preferred is phenyl.

The above definition of aryl also applies if aryl is part of another(combined) group as for example in arylamino, aryloxy or arylalkyl.

If the free valency of an aryl is saturated, then an aromatic group isobtained.

The term arylene can also be derived from the previously defined aryl.Arylene, unlike aryl, is bivalent and requires two binding partners.Formally, the second valency is formed by removing a hydrogen atom froman aryl. Corresponding groups are for example:

phenyl and

(o, m, p-phenylene),

naphthyl and

etc.

The above definition for arylene also applies if arylene is part ofanother (combined) group as for example in HO-aryleneamino orH₂N-aryleneoxy.

Heterocyclyl denotes ring systems, which are derived from the previouslydefined cycloalkyl, cycloalkenyl and aryl by replacing one or more ofthe groups —CH₂— independently of one another in the hydrocarbon ringsby the groups —O—, —S— or —NH— or by replacing one or more of the groups═CH— by the group ═N—, wherein a total of not more than five heteroatomsmay be present, at least one carbon atom must be present between twooxygen atoms and between two sulphur atoms or between an oxygen and asulphur atom and the ring as a whole must have chemical stability.Heteroatoms may optionally be present in all the possible oxidationstages (sulphur→sulphoxide—SO—, sulphone—SO₂—; nitrogen→N-oxide). In aheterocyclyl there is no heteroaromatic ring, i.e. no heteroatom is partof an aromatic system.

A direct result of the derivation from cycloalkyl, cycloalkenyl and arylis that heterocyclyl is made up of the subgroups monocyclicheterocyclyl, bicyclic heterocyclyl, tricyclic heterocyclyl andspiro-heterocyclyl, which may be present in saturated or unsaturatedform.

By unsaturated is meant that there is at least one double bond in thering system in question, but no heteroaromatic system is formed. Inbicyclic heterocyclyl two rings are linked together so that they have atleast two (hetero) atoms in common. In spiro-heterocyclyl one carbonatom (spiroatom) belongs to two rings together.

If a heterocyclyl is substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon and/or nitrogen atoms.Heterocyclyl itself may be linked as a substituent to the molecule viaevery suitable position of the ring system. Substituents on heterocyclyldo not count for the number of members of a heterocyclyl.

Examples of heterocyclyl are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl,imidazolidinyl, thiazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperidinyl, piperazinyl, oxiranyl, aziridinyl, azetidinyl,1,4-dioxanyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl,homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl,thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, 1,3-dioxolanyl,tetrahydropyranyl, tetrahydrothiopyranyl, [1,4]-oxazepanyl,tetrahydrothienyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl,dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl,dihydro-pyrimidinyl, dihydrofuryl, dihydropyranyl,tetrahydrothienyl-S-oxide, tetrahydrothienyl-S,S-dioxide,homothiomorpholinyl-S-oxide, 2,3-dihydroazet, 2H-pyrrolyl, 4H-pyranyl,1,4-dihydropyridinyl, 8-aza-bicyclo[3.2.1]octyl,8-aza-bicyclo[5.1.0]octyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,8-oxa-3-aza-bicyclo[3.2.1]octyl, 3,8-diaza-bicyclo[3.2.1]octyl,2,5-diaza-bicyclo[2.2.1]heptyl, 1-aza-bicyclo[2.2.2]octyl,3,8-diaza-bicyclo[3.2.1]octyl, 3,9-diaza-bicyclo[4.2.1]nonyl,2,6-diaza-bicyclo[3.2.2]nonyl, 1,4-dioxa-spiro[4.5]decyl,1-oxa-3,8-diaza-spiro[4.5]decyl, 2,6-diaza-spiro[3.3]heptyl,2,7-diaza-spiro[4.4]nonyl, 2,6-diaza-spiro[3.4]octyl,3,9-diaza-spiro[5.5]undecyl, 2.8-diaza-spiro[4,5]decyl etc.

Further examples are the structures illustrated below, which may beattached via each hydrogen-carrying atom (exchanged for hydrogen):

Preferred monocyclic heterocyclyl is 4 to 7 membered and has one or twoheteroatoms independently selected from oxygen, nitrogen and sulfur.

Preferred monocyclic heterocyclyls are: piperazinyl, piperidinyl,morpholinyl, pyrrolidinyl, and azetidinyl.

Preferred bicyclic heterocyclyl is 6 to 10 membered and has one or twoheteroatoms independently selected from oxygen, nitrogen and sulfur.

Preferred tricyclic heterocyclyl is 9 membered and has one or twoheteroatoms independently selected from oxygen, nitrogen and sulfur.

Preferred spiro-heterocyclyl is 7 to 11 membered and has one or twoheteroatoms independently selected from oxygen, nitrogen and sulfur.

The above definition of heterocyclyl also applies if heterocyclyl ispart of another (combined) group as for example in heterocyclylamino,heterocyclyloxy or heterocyclylalkyl.

If the free valency of a heterocyclyl is saturated, then a heterocycleis obtained.

The term heterocyclylene is also derived from the previously definedheterocyclyl. Heterocyclylene, unlike heterocyclyl, is bivalent andrequires two binding partners. Formally, the second valency is obtainedby removing a hydrogen atom from a heterocyclyl. Corresponding groupsare for example:

piperidinyl and

2,3-dihydro-1H-pyrrolyl and

etc.

The above definition of heterocyclylene also applies if heterocyclyleneis part of another (combined) group as for example inHO-heterocyclyleneamino or H₂N-heterocyclyleneoxy.

Heteroaryl denotes monocyclic heteroaromatic rings or polycyclic ringswith at least one heteroaromatic ring, which compared with thecorresponding aryl or cycloalkyl (cycloalkenyl) contain, instead of oneor more carbon atoms, one or more identical or different heteroatoms,selected independently of one another from among nitrogen, sulphur andoxygen, wherein the resulting group must be chemically stable. Theprerequisite for the presence of heteroaryl is a heteroatom and aheteroaromatic system.

If a heteroaryl is to be substituted, the substitutions may take placeindependently of one another, in the form of mono- or polysubstitutionsin each case, on all the hydrogen-carrying carbon and/or nitrogen atoms.Heteroaryl itself may be linked as a substituent to the molecule viaevery suitable position of the ring system, both carbon and nitrogen.Substituents on heteroaryl do not count for the number of members of aheteroaryl.

Examples of heteroaryl are furyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl, pyridyl-N-oxide, pyrrolyl-N-oxide,pyrimidinyl-N-oxide, pyridazinyl-N-oxide, pyrazinyl-N-oxide,imidazolyl-N-oxide, isoxazolyl-N-oxide, oxazolyl-N-oxide,thiazolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide,triazolyl-N-oxide, tetrazolyl-N-oxide, indolyl, isoindolyl, benzofuryl,benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl,quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, benzotriazinyl,indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl,benzoxazolyl, pyridopyridyl, pyrimidopyridyl, purinyl, pteridinyl,benzothiazolyl, imidazopyridyl, imidazothiazolyl, quinolinyl-N-oxide,indolyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide,quinoxalinyl-N-oxide, phthalazinyl-N-oxide, indolizinyl-N-oxide,indazolyl-N-oxide, benzothiazolyl-N-oxide, benzimidazolyl-N-oxide etc.

Further examples are the structures illustrated below, which may beattached via each hydrogen-carrying atom (exchanged for hydrogen):

Preferably, heteroaryls are 5-6 membered monocyclic or 9-10 memberedbicyclic, each with 1 to 4 heteroatoms independently selected fromoxygen, nitrogen and sulfur.

The above definition of heteroaryl also applies if heteroaryl is part ofanother (combined) group as for example in heteroarylamino,heteroaryloxy or heteroarylalkyl.

If the free valency of a heteroaryl is saturated, a heteroaromatic groupis obtained.

The term heteroarylene is also derived from the previously definedheteroaryl.

Heteroarylene, unlike heteroaryl, is bivalent and requires two bindingpartners. Formally, the second valency is obtained by removing ahydrogen atom from a heteroaryl.

Corresponding groups are for example:

pyrrolyl and

etc.

The above definition of heteroarylene also applies if heteroarylene ispart of another (combined) group as for example in HO-heteroaryleneaminoor H₂N-heteroaryleneoxy.

By substituted is meant that a hydrogen atom which is bound directly tothe atom under consideration, is replaced by another atom or anothergroup of atoms (substituent). Depending on the starting conditions(number of hydrogen atoms) mono- or polysubstitution may take place onone atom. Substitution with a particular substituent is only possible ifthe permitted valencies of the substituent and of the atom that is to besubstituted correspond to one another and the substitution leads to astable compound (i.e. to a compound which is not convertedspontaneously, e.g. by rearrangement, cyclisation or elimination).

Bivalent substituents such as ═S, ═NR, ═NOR, ═NNRR, ═NN(R)C(O)NRR, ═N₂or the like, may only be substituents on carbon atoms, whereas thebivalent substituents ═O and ═NR may also be a substituent on sulphur.Generally, substitution may be carried out by a bivalent substituentonly at ring systems and requires replacement of two geminal hydrogenatoms, i.e. hydrogen atoms that are bound to the same carbon atom thatis saturated prior to the substitution. Substitution by a bivalentsubstituent is therefore only possible at the group —CH₂— or sulphuratoms (═O group or ═NR group only, one or two ═O groups possible or,e.g., one ═O group and one ═NR group, each group replacing a freeelectron pair) of a ring system.

Stereochemistry/solvates/hydrates: Unless specifically indicated,throughout the specification and appended claims, a given chemicalformula or name shall encompass tautomers and all stereo, optical andgeometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers, etc.)and racemates thereof as well as mixtures in different proportions ofthe separate enantiomers, mixtures of diastereomers, or mixtures of anyof the foregoing forms where such isomers and enantiomers exist, as wellas salts, including pharmaceutically acceptable salts thereof andsolvates thereof such as for instance hydrates including solvates andhydrates of the free compound or solvates and hydrates of a salt of thecompound.

In general, substantially pure stereoisomers can be obtained accordingto synthetic principles known to a person skilled in the field, e.g. byseparation of corresponding mixtures, by using stereochemically purestarting materials and/or by stereoselective synthesis. It is known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis, e.g. starting from optically activestarting materials and/or by using chiral reagents.

Enantiomerically pure compounds of this invention or intermediates maybe prepared via asymmetric synthesis, for example by preparation andsubsequent separation of appropriate diastereomeric compounds orintermediates which can be separated by known methods (e.g. bychromatographic separation or crystallization) and/or by using chiralreagents, such as chiral starting materials, chiral catalysts or chiralauxiliaries.

Further, it is known to the person skilled in the art how to prepareenantiomerically pure compounds from the corresponding racemic mixtures,such as by chromatographic separation of the corresponding racemicmixtures on chiral stationary phases, or by resolution of a racemicmixture using an appropriate resolving agent, e.g. by means ofdiastereomeric salt formation of the racemic compound with opticallyactive acids or bases, subsequent resolution of the salts and release ofthe desired compound from the salt, or by derivatization of thecorresponding racemic compounds with optically active chiral auxiliaryreagents, subsequent diastereomer separation and removal of the chiralauxiliary group, or by kinetic resolution of a racemate (e.g. byenzymatic resolution); by enantioselective crystallization from aconglomerate of enantiomorphous crystals under suitable conditions, orby (fractional) crystallization from a suitable solvent in the presenceof an optically active chiral auxiliary.

Salts: The phrase “pharmaceutically acceptable” is employed herein torefer to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgement, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, and commensurate with a reasonable benefit/risk ratio.

As used herein “pharmaceutically acceptable salts” refers to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like.

For example, such salts include salts from benzenesulfonic acid, benzoicacid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid,hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonicacid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonicacid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid andtartaric acid.

Further pharmaceutically acceptable salts can be formed with cationsfrom ammonia, L-arginine, calcium, 2,2′-iminobisethanol, L-lysine,magnesium, N-methyl-D-glucamine, potassium, sodium andtris(hydroxymethyl)-aminomethane.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base form of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example areuseful for purifying or isolating the compounds of the present invention(e.g. trifluoro acetate salts), also comprise a part of the invention.

In a representation such as for example

the letter A has the function of a ring designation in order to make iteasier, for example, to indicate the attachment of the ring in questionto other rings.

For bivalent groups in which it is crucial to determine which adjacentgroups they bind and with which valency, the corresponding bindingpartners are indicated in brackets where necessary for clarificationpurposes, as in the following representations:

or (R²)—C(═O)NH— or (R²)—NHC(═O)—.

If such a clarification is missing then the bivalent group can bind inboth directions, i.e., e.g., —C(═O)NH— also includes—NHC(═O)— (and viceversa).

Groups or substituents are frequently selected from among a number ofalternative groups/substituents with a corresponding group designation(e.g. R^(a), R^(b) etc). If such a group is used repeatedly to define acompound according to the invention in different parts of the molecule,it is pointed out that the various uses are to be regarded as totallyindependent of one another.

By a therapeutically effective amount for the purposes of this inventionis meant a quantity of substance that is capable of obviating symptomsof illness or of preventing or alleviating these symptoms, or whichprolong the survival of a treated patient.

Ras family proteins as used herein is meant to include KRAS (V-Ki-ras2Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RASviral oncogene homolog) and HRAS (Harvey murine sarcoma virus oncogene)and any mutants thereof.

A RAS G12C inhibitor as used herein refers to a compound, which binds toone or more of the G12C mutant RAS proteins KRAS G12C(=KRAS G12Cinhibitor), NRAS G12C (=NRAS G12C inhibitor) and/or HRAS G12C (=HRASG12C inhibitor), in particular to KRAS G12C, and is capable ofnegatively modulating or inhibiting all or a portion of the enzymaticactivity of KRAS G12C and/or NRAS G12C and/or HRAS G12C, in particularof KRAS G12C. While not wishing to be bound by theory, it is believedthat the compounds of the invention may selectively react with KRAS G12Cand/or HRAS G12C and/or NRAS G12C proteins (preferably with KRAS G12C)by forming a covalent bond with the cysteine at the 12 position of KRASG12C and/or HRAS G12C and/or NRAS G12C (preferably of KRAS G12C)resulting in the modulation/inhibition of the enzymatic activity ofthese mutant Ras proteins.

List of abbreviations

Ac acetyl ACN acetonitrile aq. aquatic, aqueous ATP adenosinetriphosphate Bn benzyl Boc tert-butyloxycarbonyl Bu butyl cconcentration Cbz carboxybenzyl CDI 1,1′-carbonyldiimidazole d day(s)TLC thin layer chromatography Davephos2-dimethylamino-2′-dicyclohexylaminophosphinobiphenyl DBU1,8-Diazabicyclo(5.4.0)undec-7-ene DCE dichloro ethane DCM dichloromethane DEA diethyl amine DIPEA N-ethyl-N,N-diisopropylamine (Hünig'sbase) DMA dimethylacetamide DMAP 4-N,N-dimethylaminopyridine DME1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulphoxideDPPA diphenylphosphorylazide dppf 1,1′-bis(diphenylphosphino)ferroceneEDTA ethylenediaminetetraacetic acid EGTA ethyleneglycoltetraacetic acideq. equivalent(s) ESI electron spray ionization Et ethyl Et₂O diethylether EtOAc ethyl acetate EtOH ethanol h hour HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl- uroniumhexafluorophosphate HPLC high performance liquid chromatography i isoconc. concentrated LC liquid chromatography LiHMDS lithiumbis(trimethylsilyl)amide sln. solution Me methyl MeOH methanol minminutes MPLC medium pressure liquid chromatography MS mass spectrometryMTBE methyl tert-butyl ether NMM N-methylmorpholine NMPN-methylpyrrolidone NP normal phase n.a. not available PBSphosphate-buffered saline Ph phenyl Pr propyl PTSA p-toluenesulfonicacid Py pyridine rac racemic red. reduction Rf (R_(f)) retention factorRP reversed phase RRLC Rapid resolution liquid chromatography rt ambienttemperature SFC supercritical fluid chromatography S_(N) nucleophilicsubstitution TBAF tetrabutylammonium fluoride TBDMStert-butyldimethylsilyl TBME tert-butylmethylether TBTUO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium tetrafluoroboratetBu tert-butyl TEA triethyl amine temp. temperature tert tertiary Tftriflate TFA trifluoroacetic acid THF tetrahydrofuran TMS trimethylsilylt_(Ret.) retention time (HPLC) TRIS tris(hydroxymethyl)-aminomethaneTsOH p-toluenesulphonic acid UPLC ultra performance liquidchromatography UV ultraviolet wt weight

Examples

Features and advantages of the present invention will become apparentfrom the following detailed examples which illustrate the principles ofthe invention by way of example without restricting its scope:

Preparation of the Compounds According to the Invention

General

Unless stated otherwise, all the reactions are carried out incommercially obtainable apparatus using methods that are commonly usedin chemical laboratories. Starting materials that are sensitive to airand/or moisture are stored under protective gas and correspondingreactions and manipulations therewith are carried out under protectivegas (nitrogen or argon).

If a compound is to be represented both by a structural formula and byits nomenclature, in the event of a conflict the structural formula isdecisive.

Microwave reactions are carried out in an initiator/reactor made byBiotage or in an Explorer made by CEM or in Synthos 3000 or Monowave3000 made by Anton Paar in sealed containers (preferably 2, 5 or 20 mL),preferably with stirring.

Chromatography

The thin layer chromatography is carried out on ready-made silica gel 60TLC plates on glass (with fluorescence indicator F-254) made by Merck.

The preparative high pressure chromatography (RP HPLC) of the examplecompounds according to the invention is carried out on Agilent or Gilsonsystems with columns made by Waters (names: SunFire™ Prep C18, OBD™ 10μm, 50×150 mm or SunFire™ Prep C18 OBD™ 5 μm, 30×50 mm or XBridge™ PrepC18, OBD™ 10 μm, 50×150 mm or XBridge™ Prep C18, OBD™ 5 μm, 30×150 mm orXBridge™ Prep C18, OBD™ 5 μm, 30×50 mm) and YMC (names: Actus-TriartPrep C18, 5 μm, 30×50 mm).

Different gradients of H₂O/acetonitrile are used to elute the compounds,while for Agilent systems 5% acidic modifier (20 mL HCOOH to 1 LH₂O/acetonitrile (1/1)) is added to the water (acidic conditions). ForGilson systems the water is added 0.1% HCOOH.

For the chromatography under basic conditions for Agilent systemsH₂O/acetonitrile gradients are used as well, while the water is madealkaline by addition of 5% basic modifier (50 g NH₄HCO₃+50 mL NH₃ (25%in H₂O) to 1 L with H₂O). For Gilson systems the water is made alkalineas follows: 5 mL NH₄HCO₃ solution (158 g in 1 L H₂O) and 2 mL NH₃ (28%in H₂O) are replenished to 1 L with H₂O.

The supercritical fluid chromatography (SFC) of the intermediates andexample compounds according to the invention is carried out on a JASCOSFC-system with the following colums: Chiralcel OJ (250×20 mm, 5 μm),Chiralpak AD (250×20 mm, 5 μm), Chiralpak AS (250×20 mm, 5 μm),Chiralpak IC (250×20 mm, 5 μm), Chiralpak IA (250×20 mm, 5 μm),Chiralcel OJ (250×20 mm, 5 μm), Chiralcel OD (250×20 mm, 5 μm),Phenomenex Lux C2 (250×20 mm, 5 μm).

The analytical HPLC (reaction control) of intermediate and finalcompounds is carried out using columns made by Waters (names: XBridge™C18, 2.5 μm, 2.1×20 mm or XBridge™ C18, 2.5 μm, 2.1×30 mm or Aquity UPLCBEH C18, 1.7 μm, 2.1×50 mm) and YMC (names: Triart C18, 3.0 μm, 2.0×30mm) and Phenomenex (names: Luna C18, 5.0 μm, 2.0×30 mm). The analyticalequipment is also equipped with a mass detector in each case.

HPLC-mass spectroscopy/UV-spectrometry

The retention times/MS-ESI⁺ for characterizing the example compoundsaccording to the invention are produced using an HPLC-MS apparatus (highperformance liquid chromatography with mass detector). Compounds thatelute at the injection peak are given the retention time t_(Ret.)=0.00.

SFC-Method (preparative)

Preparative SFC is performed in Waters Thar SFC 80 system

-   -   Column: Chiralpak AD-H (21×250 mm), 5 μm    -   Flow: 25 g/min    -   Mobile Phase: 75% CO₂+25% MeOH (0.5% isopropylamine)    -   ABPR: 120 bar    -   Temp: 35° C.    -   UV: 220 nm    -   Stack Time: 8 min

HPLC-Methods (analytic)

Method A

Samples were analyzed on an Agilent 1200 series LC system coupled withan Agilent 6140 mass spectrometer. Purity was determined via UVdetection with a bandwidth of 170 nm in the range from 230-400 nm. LCparameters were as follows:

column Waters Xbridge C18 column 3.5 μm particle size, 2.1 × 30 mm; flow1 mL/min; column temperature 60° C.; injection 5 μL injections; solventA: 20 mM NH₄HCO₃/NH₃ pH 9 B: MS grade acetonitrile; gradient 0.0-1.5 min10%-95% B 1.5-2.0 min 95% B 2.0-2.1 min 95%-10% B

Method B

HPLC Agilent 1100/1200 Series MS Agilent LC/MSD SL column WatersX-Bridge BEH C18, 2.5 μm, 2.1 × 30 mm XP solvent A: 20 mM NH₄HCO₃/28 mMNH₃ in H₂O; B: acetonitrile (HPLC grade) detection MS: positive andnegative mode mass range 100-750 m/z flow 1.40 mL/min column temperature45° C. gradient: 0.00-1.00 min: 15% B → 95% B 1.00-1.30 min: 95% B

Method C

HPLC Agilent 1100/1200 Series MS Agilent LC/MSD SL column Waters SunFireC18, 2.5 μm, 2.1 × 30 mm XP solvent A: 0.1% HCOOH in H₂O; B: 0.1% HCOOHin acetonitrile (HPLC grade) detection MS: positive and negative modemass range 150-750 m/z flow 1.40 mL/min column temperature 45° C.gradient 0.00-1.00 min: 15% B → 100% B 1.00-1.13 min: 100% B

Method D

HPLC Agilent 1100/1200 system MS 1200 Series LC/MSD (MM-ES + APCI +/−3000 V, Quadrupol, G6130B) MSD signal settings Scan pos 150-750 columnWaters, Part. No. 186003389, XBridge BEH C18, 2.5 μm, 2.1 × 30 mm)column eluent A: 5 mM NH₄HCO₃/18 mM NH₃ (pH = 9.2) B: acetonitrile (HPLCgrade) detection signal UV 254 nm, 230 nm, 214 nm (bandwidth 8,reference off) spectrum range: 190-400 nm; slit: 4 nm peak width >0.0031min (0.063 s response time, 80 Hz) injection 0.5 μL standard injectionflow 1.4 mL/min column temperature 45° C. gradient 0.0-1.0 min 15% → 95%B 1.0-1.1 min 95% B Stop time: 1.3 min

Method E

HPLC Agilent 1100/1200 system MS 1200 Series LC/MSD (API-ES +/−3000/3500 V, Quadrupol, G6140A) MSD signal settings Scan pos 150-750column YMC; Part. No. TA12S03-0302WT; Triart C18, 3 μm, 12 nm; 30 × 2.0mm column eluant A: H₂O + 0.11% formic acid B: MeCN + 0.1% formic acid(HPLC grade) detection signal UV 254 nm, 230 nm, 214 nm (bandwidth 10,reference off) spectrum range: 190-400 nm; slit: 4 nm peak width >0.0031min (0.063 s response time, 80 Hz) injection 0.5 μL standard injectionflow 1.4 mL/min column temperature 45° C. gradient 0.0-1.0 min 15% → 95%B 1.0-1.1 min 95% B Stop time: 1.23 min

Method F

HPLC Agilent 1100/1200 system MS 1200 Series LC/MSD (API-ES +/−3000/3500 V, Quadrupol, G6140A) MSD signal settings Scan pos/neg 150-750column YMC; Part. No. TA12S03-0302WT; Triart C18, 3 μm, 12 nm; 30 × 2.0mm column eluant A: H₂O + 0.11% formic acid B: MeCN + 0.1% formic acid(HPLC grade) detection signal UV 254 nm, 230 nm, 214 nm (bandwidth 10,reference off) spectrum range: 190-400 nm; slit: 4 nm peak width >0.0031min (0.063 s response time, 80 Hz) injection 0.5 μL standard injectionflow 1.4 mL/min column temperature 45° C. gradient 0.0-1.0 min 15% → 95%B 1.0-1.1 min 95% B Stop time: 1.23 min

Method G

HPLC Agilent 1100/1200 system MS 1200 Series LC/MSD (MM-ES + APCI +/−3000 V, Quadrupol, G6130B) MSD signal settings Scan pos/neg 150-750column Waters, Part.No. 186003389, XBridge BEH C18, 2.5 μm, 2.1 × 30 mm)column eluant A: 5 mM NH₄HCO₃/18 mM NH₃ (pH = 9.2) B: acetonitrile (HPLCgrade) detection signal UV 254 nm, 230 nm, 214 nm (bandwidth 8,reference off) spectrum range: 190-400 nm; slit: 4 nm peak width >0.0031min (0.063 s response time, 80 Hz) injection 0.5 μL standard injectionflow 1.4 mL/min column temperature 45° C. gradient 0.0-1.0 min 15% → 95%B 1.0-1.1 min 95% B Stop time: 1.3 minThe compounds according to the invention and intermediates are preparedby the methods of synthesis described hereinafter in which thesubstituents of the general formulae have the meanings givenhereinbefore. These methods are intended as an illustration of theinvention without restricting its subject matter and the scope of thecompounds claimed to these examples. Where the preparation of startingcompounds is not described, they are commercially obtainable or theirsynthesis is described in the prior art or they may be preparedanalogously to known prior art compounds or methods described herein,i.e. it is within the skills of an organic chemist to synthesize thesecompounds. Substances described in the literature can be preparedaccording to the published methods of synthesis. If a chemical structurein the following is depicted without exact configuration of a stereocenter, e.g. of an asymmetrically substituted carbon atom, then bothconfigurations shall be deemed to be included and disclosed in such arepresentation. The representation of a stereo center in racemic formshall always deem to include and disclose both enantiomers (if no otherdefined stereo center exists) or all other potential diastereomers andenantiomers (if additional, defined or undefined, stereo centers exist).

General reaction schemes and summary of the syntheses routes towardscompounds (1) according to the invention

Experimental Procedure for the Synthesis of A-2a

To a suspension of sodium hydride, (60% in mineral oil, 25.85 g, 646.3mmol, 1.1 eq.) in THF (2.0 L) is added A-1a (93.46 mL, 587.5 mmol, 1.0eq.) dropwise at 0-10° C. The mixture is stirred at 10° C. for 30 min,then methyl iodide (55.11 mL, 881.3 mmol. 1.5 eq.) is added to themixture dropwise at 10° C. The mixture is allowed to reach rt overnight.After complete conversion the reaction mixture is cooled to 0° C. andquenched with saturated aq. ammonium chloride solution. The product isextracted with EtOAc and the combined organic layers are washed withwater and brine, dried over sodium sulfate and concentrated underreduced pressure to afford A-2a which is used for the next step withoutfurther purification.

The following intermediates A-2 (table 1) are available in an analogousmanner using different cyclic p-keto esters A-1. The crude product A-2is purified by chromatography if necessary.

TABLE 1 # structure t_(ret) [min] [M + H]⁺ HPLC method A-2a

1.14 185 A A-2b

1.19 199 A A-2c

0.96 171 A

Experimental Procedure for the Synthesis of A-3a

To a solution of A-2a (108.00 g, 586.2 mmol) in toluene (1.03 L) isadded malononitrile (58.04 g, 879.3 mmol, 1.5 eq.) followed by ammoniumacetate (9.04 g, 117.2 mmol, 0.2 eq.) and acetic acid (13.41 mL, 234.5mmol, 0.4 eq.) at rt. The mixture is stirred at 110° C. for 16 h. Aftercomplete conversion the mixture is diluted with EtOAc and washed withwater and brine, dried over sodium sulfate and concentrated underreduced pressure to afford the crude product A-3a. This crude materialis used for the next step without further purification (see also Naumannet al., Pharmazie 51 (1996), 4).

The following intermediates A-3 (table 2) are available in an analogousmanner using different intermediates A-2. The crude product A-3 ispurified by chromatography if necessary.

TABLE 2 HPLC # structure t_(ret) [min] [M +H ]⁺ method A-3a

n.a. n.a. — A-3b

1.34 245 A A-3c

n.a. n.a. —

Experimental Procedure for the Synthesis of A-4a

To a solution of A-3a (250.0 g, 1.1 mol) in DMF (3.0 L) is added sulphur(68.9 g, 2.2 mol, 2.0 eq.) and L-proline (24.8 g, 0.22 mol, 0.2 eq.) andthe resulting mixture is stirred at 80° C. for 12 h. After completeconversion the mixture is partitioned between EtOAc and water and theorganic layer is collected. The aqueous layer is further extracted withEtOAc and the combined organic layers are washed with water and brine,dried over sodium sulfate and concentrated under reduced pressure toafford the crude product. The crude product is purified through columnchromatography yielding A-4a.

The following intermediates A-4 (table 3) are available in an analogousmanner using different intermediates A-3. The crude product A-4 ispurified by chromatography if necessary.

TABLE 3 # structure t_(ret) [min] [[M +H ]⁺ HPLC method A-4a

1.08 265 A A-4b

1.25 279 A A-4c

n.a. n.a. —

Experimental Procedure for the Synthesis of A-4d

A stirred solution of A-1a (12.00 g, 70.5 mmol) in EtOH (60.0 mL) istreated with sulfur (2.26 g, 70.5 mmol, 1.00 eq.), morpholine (6.14 g,70.5 mmol, 1.0 eq.) and malononitrile (4.66 g, 70.5 mmol, 1.0 eq.). Thenthe reaction mixture is stirred at 55° C. for 1 h. After completeconversion the reaction mixture is concentrated, diluted with water,extracted with EtOAc and the extracts are dried, filtered andconcentrated under reduced pressure to get crude product. This crudematerial is purified by column chromatography (20-30% EtOH in hexane) toafford A-4d. (HPLC method A; t_(ret)=1.10 min; [M+H]⁺=251).

Experimental Procedure for the Synthesis of A-5a

A-4a (78.0 mg, 0.3 mmol, 1.0 eq.) is dissolved in EtOH (1.5 mL) andpotassium hydroxide (4 M in water, 0.37 mL, 1.5 mmol, 5.0 eq.) is added.The mixture is stirred for 16 h at 78° C. After complete conversion,water and EtOAc is added to the mixture, the pH of the aqueous phase isset to pH 4 using KHSO₄ solution (10% in water), and the product isextracted using EtOAc. The combined organic layers are dried, filteredand concentrated. The crude product is purified via acidic reversedphase chromatography (gradient elution: 20% to 90% acetonitrile inwater) yielding A-5a.

The following intermediates A-5 (table 4) are available in an analogousmanner using different esters A-4. The crude product A-5 is purified bychromatography if necessary, enantiomers can be separated withpreparative SFC chromatography as herein described, e.g. separation ofA-5a into A-5b and its enantiomer.

TABLE 4 HPLC # structure t_(ret) [min] [M + H]⁺ method A-5a

0.22 237 A A-5b

0.25 237 A A-5c

0.43 251 A A-5d

n.a. n.a. — A-5e

0.18 223 A A-5f

n.a. n.a. — A-5g

0.09 223 B A-5h

n.a. n.a. —

Experimental Procedure for the Synthesis of E-2a

To a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)-ethan-1-ol (1.441g, 11.15 mmol, 1.0 eq.) in DMSO is added DIPEA (2.882 g, 22.3 mmol, 2.0eq.) and the mixture is cooled to 10° C. E-1a (2.0 g, 11.15 mmol, 97%purity, 1.0 eq.) is added and the mixture is stirred at 10° C. for 45min. The mixture is filtered and the filtrate is purified via basicreversed phase chromatography (gradient elution: 30% to 98% acetonitrilein water) yielding E-2a. (HPLC method A; t_(ret)=1.36 min; [M+H]⁺=267).

Additional intermediates E-2 are available in an analogous manner. Thecrude product E-2 can be purified by chromatography if necessary.

Experimental Procedure for the Synthesis of E-2b

E-3a (3.50 g, 15.9 mmol) is dissolved in DMF (10 mL).2-dimethylaminoethyl chloride HCl salt (6.87 g, 47.72 mmol) is added andthe mixture stirred for 25 min at 150° C. The mixture is cooled to rtand filtered through a glass frit then washed with EtOAc. The solvent isremoved by lyophilization. The residue is purified by normal phasechromatography (gradient elution: 0% to 20% MeOH in DCM) yielding E-2b.

The following intermediates E-2 (table 5) are available in an analogousmanner. The crude product E-2 is purified by chromatography ifnecessary.

TABLE 5 # structure t_(ret) [min] [M + H]⁺ HPLC method E-2b

1.11 268 A E-2c

1.21 283 A E-2d

1.22 295 A

Experimental Procedure for the Synthesis of E-4a (Method A)

4-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.76 g, 13.73mmol) and cesium carbonate (2.76 g, 13.73 mmol) are dissolved in DMA (10mL). E-1b (2.50 g, 13.73 mmol) is added and the mixture stirred at 90°C. for 1 h. The reaction mixture is extracted from water into EtOAc andthe organic phase dried over magnesium sulfate. The solvent is removedin vacuo and the residue purified via basic reversed phasechromatography (gradient elution: 45% to 98% acetonitrile in water)yielding E-4a.

Experimental Procedure for the Synthesis of E-4b (Method B)

To a stirred solution of E-1b (5.00 g, 28.90 mmol) in DMSO (50.0 mL) isadded piperazine-1-carboxylic acid tert-butyl ester (5.92 g, 31.79 mmol,1.1 eq.). Then DIPEA (11.21 g, 86.71 mmol, 3.0 eq.) is added and thereaction mixture is stirred at 60° C. for 1 h. After complete conversionthe mixture is dissolved in EtOAc and washed with water (3×). Theorganic phase is dried, filtered and concentrated under reducedpressure. The crude product is purified via column chromatography(EtOAc/hexane) yielding E-4b.

Experimental Procedure for the Synthesis of E-4c (Method C)

To a stirred solution of E-1c (10.20 g, 57.22 mmol) in DCM (60.0 mL) isadded piperazine-1-carboxylic acid tert-butyl ester (11.22 g, 57.22mmol, 1.0 eq.). Then DIPEA (20.71 g, 160.21 mmol, 2.8 eq.) is added andthe reaction mixture is stirred at 60° C. for 1 h. After completeconversion the mixture is dissolved in EtOAc and washed with water (3×).The organic phase is dried, filtered and concentrated under reducedpressure. The crude product is purified via column chromatography(DCM/MeOH) yielding E-4c.

Experimental Procedure for the Synthesis of E-4d (Method D)

To a stirred mixture of sodium hydride (22.8 mg, 0.95 mmol, 1.1 eq.) andTHF (2 mL) under argon is added tert-butylN—(2-hydroxyethyl)-N-methylcarbamate (171 mg, 0.95 mmol, 1.1 eq.) at rtand the mixture is stirred for 5 min. E-1c (150 mg, 0.86 mmol, 1.0 eq.)is added and the mixture is stirred for 1 h. The reaction is quenched byaddition of a few drops of water and solvents are removed under vacuum.The crude product is dissolved in DCM and purified via columnchromatography (DCM/MeOH) yielding E-4d.

Experimental Procedure for the Synthesis of E-4e (Method E)

E-1d (1.00 g, 6.62 mmol), piperazine-1-carboxylic acid tert-butyl ester(724.6 mg, 3.70 mmol, 0.8 eq.), sodium tert-butoxide (915.4 mg, 9.24mmol, 2.0 eq.), 2-(di-tert-butylphosphino)biphenyl (275.7 mg, 0.92 mmol,0.20 eq.), and tris(dibenzylideneacetone)dipalladium(0) (211.5 mg, 0.23mmol, 0.05 eq.) are combined in dry dioxane (9.00 mL) and the mixture isstirred for 1 h at rt. After complete conversion the mixture isconcentrated, diluted with water, the product is extracted with DCM andthe combined organic layers are dried, filtered, and concentrated. Thecrude product is purified via basic reversed phase chromatography(gradient elution: 35% to 98% acetonitrile in water) yielding E-4e.

The following (additional) intermediates E-4 (table 6) are available inan analogous manner using different amines PG-L-H and intermediates E-1according to methods A to E. The crude products E-4 can be purified bychromatography if necessary.

TABLE 6 # method structure t_(ret) [min] [M + H]⁺ HPLC method E-4a A

1.43 338 A E-4b B

0.73 323 B E-4c C

0.72 324 F E-4d D

0.71 213 (M-Boc) F E-4e E

0.83 266 B E-4f A

1.44 338 A E-4g B

0.72 357 B E-4h B

1.36 338 A E-4i B

0.71 338 F E-4j C

1.57 352 A E-4k C

0.75 338 G E-4l C

n.a. n.a. — E-4m C

1.48 352 A E-4n C

1.49 350 A E-4o C

1.41 352 A E-4p C

1.44 350 A E-4q C

0.79 364 G E-4r C

1.43 338 A E-4s C

1.49 352 A E-4t C

0.72 324 F E-4u B

0.76 364 B E-4v B

1.34 338 A E-4w B

1.42 350 A E-4x B

1.40 350 A E-4y B

1.41 364 A E-4z B

0.70 350 A E-4aa B

1.47 376 A E-4ab B

1.34 377 (M-Boc) A E-4ac B

1.31 377 (M-Boc) A E-4ad B

1.28 336 A E-4ae B

1.57 346 A E-4af B

1.42 350 A E-4ag B

1.36 337 A E-4ah B

1.19 323 A E-4ai B

0.72 357 B E-4aj A

0.72 324 F E-4ak B

1.22 337 A E-4al B

0.72 324 F E-4am B

1.48 352 A E-4an B

1.29 349 A E-4ao A

1.39 350 A E-4ap A

0.77 324 F

Experimental Procedure for the Synthesis of E-6a

E-1b (500 mg, 2.83 mmol, 1.0 eq.) and cesium fluoride (1.72 g, 11.33mmol, 4.0 eq.) are dissolved in DMA (5 mL) and heated to 110° C. bymicrowave irradiation. The mixture is filtered and the solid is washedwith a small amount of DMA to give a crude solution of E-5a in DMA.

To a solution of (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butylester (531 mg, 187.24 mmol, 1.0 eq.) in THF (5 mL) is added sodiumhydride (158 mg, 3.97 mmol, 1.4 eq.) and the mixture is stirred for 30min. This mixture is added slowly to the freshly prepared solution ofE-5a (397 mg, 140.09 mmol, 1.0 eq.) in DMA and stirred for 5 min beforewater and EtOAc are added. The phases are separated and the aqueousphase is extracted twice with EtOAc (30 mL). The combined organic layeris dried with MgSO₄, filtered and the solvents are evaporated. Themixture is dissolved in acetonitrile and water and purified by acidicreversed phase chromatography to give the desired product E-6a.

The following intermediates E-6 (table 7) are available in an analogousmanner. The crude product E-7 is purified by chromatography ifnecessary.

TABLE 7 # structure t_(ret) [min] [M + H]⁺ HPLC method E-6a

1.32 308 A E-6b

0.68 252 (M-tBu) F E-6c

1.52 294 A

Experimental Procedure for the Synthesis of E-6d

E-1b (267 mg, 1.54 mmol, 1.0 eq.) and cesium fluoride (937 mg, 6.17mmol, 4.0 eq.) are dissolved in DMA (3 mL) and heated to 110° C. bymicrowave irradiation. The mixture is filtered and the solid is washedwith a small amount of DMA to give a crude solution of E-5a in DMA.Tert-butyl 5,8-diazaspiro[3.5]nonane-4-carboxylate (349 mg, 1.54 mmol,1.0 eq.) and DIPEA (0.667 mL, 3.86 mmol, 2.5 eq.) are added to themixture which is stirred at 60° C. for 30 min. The mixture is filteredand the filtrate purified by basic reversed phase chromatography to givethe desired product E-6d.

The following intermediates E-6 (table 8) are available in an analogousmanner. The crude product E-6 is purified by chromatography ifnecessary.

TABLE 8 t_(ret) HPLC # structure [min] [M + H]⁺ method E-6d

0.77 347 G E-6e

0.80 361 G

Experimental Procedure for the Synthesis of E-6f

Intermediate E-4ap (60 mg, 0.19 mmol, 1.0 eq.) and cesium fluoride (56mg, 0.37 mmol, 2.0 eq.) are dissolved in DMSO (2 mL) and stirred at 80°C. over night and cooled to rt. Additional cesium fluoride (56 mg, 0.37mmol, 2.0 eq.) is added and the mixture is stirred at 110° C. tocomplete the reaction. Water and acetonitrile are added and the mixtureis purified by acidic reversed phase chromatography to give the desiredproduct E-6f.

The following intermediates E-6 (table 9) are available in an analogousmanner from other intermediates E-4. The crude product E-6 is purifiedby chromatography if necessary.

TABLE 9 t_(ret) [M + HPLC # structure [min] H]⁺ method E-6f

0.73 308 F E-6g

1.26 307 A

Synthesis of Various Building Blocks H-R⁵

Experimental Procedure for the Synthesis of G-2a

G-1a (500 mg, 2.33 mmol) is dissolved in dry THF (5.00 mL) together withtriethylamine (485 μL, 3.5 mmol, 1.5 eq.) and the mixture is cooled to0° C. Benzyl chlorformate (519 μL, 3.5 mmol, 1.5 eq.) is addedportionwise and the mixture is stirred for 2 h and allowed to reach rtover night. After complete conversion water is added to the mixture andthe product is extracted with DCM and the combined extracts are dried,filtered and concentrated. The crude product is used for the next stepwithout further purification. (HPLC method B, t_(ret)=0.766 min,[M+H]*=249/293).

Experimental Procedure for the Synthesis of G-3a

G-2a (813 mg, 2.33 mmol) is dissolved in DCM (25.00 mL) and treated withHCl (4 M in dioxane, 11.67 mL, 46.66 mmol, 20.0 eq.). The mixture isstirred for 2 h at rt. After complete conversion the mixture isconcentrated and the product is isolated via basic reversed phasechromatography (gradient elution: 10% to 70% acetonitrile in water).(HPLC method B, t_(ret)=0.478 min, [M+H]⁺=249).

Experimental Procedure for the Synthesis of G-4a (Method F)

G-3a (4.0 g, 16.12 mmol) is dissolved in dry DCM (50.00 mL) and treatedwith formaldehyde (37% in water, 1.21 mL, 16.12 mmol, 1.00 eq.) andacetic acid (92 μL, 1.61 mmol, 0.10 eq.). The mixture is stirred for 15min and then sodium triacetoxyborohydride (6.335 g, 29.00 mmol, 1.80eq.) is added and the mixture is stirred for 1 h at rt. After completeconversion water is added to the mixture and the product is extractedwith DCM and the combined extracts are dried, filtered and concentrated.The crude product is purified via normal phase chromatography(DCM/MeOH).

Experimental Procedure for the Synthesis of G-4b (Method G)

To a stirred solution of G-3a (250.0 mg, 1.00 mmol) in dry DMF (5.00mL), K₂CO₃ (0.303 g, 2.51 mmol, 2.50 eq.) is added followed by1-bromo-2-methoxy-ethane (0.122 g, 1.00 mmol, 1.00 eq.). The reactionmixture is stirred at 80° C. for 16 h. After complete conversion wateris added to the mixture and the product is extracted with EtOAc and thecombined extracts are dried, filtered, and concentrated. The crudeproduct is purified via normal phase chromatography (DCM/MeOH).

The following (additional) intermediates G-4 (table 10) are available inan analogous manner using G-3a and different aldehydes or ketones asalkylating agents according to methods F or G. The crude products G-4can be purified by chromatography if necessary.

TABLE 10 # structure method t_(ret) [min] [M + H]⁺ HPLC method G-4a

A  0.557 263 B G-4b

B n.a. n.a. — G-4c

B n.a. n.a. — G-4d

A 1.34 333 A G-4e

A 1.20 319 A

Experimental Procedure for the Synthesis of G-5a

G-5a (3.00 g, 11.44 mmol) is dissolved in MeOH (20.0 mL) and palladium(10% on carbon, 360 mg) is added. The mixture is stirred in ahydrogenation reactor under 5 bar of hydrogen pressure for 16 h at rt.After complete conversion the catalyst is filtered off and the residueis concentrated. The crude product is used for the following stepwithout purification.

The following intermediates G-5 (≙ building bocks H—R⁵; table 11) areavailable in an analogous manner using differently substituted analoguesG-4.

TABLE 11 t_(ret) [M + HPLC # structure [min] H]⁺ method G-5a

broad 129 A G-5b

n.a. n.a. — G-5c

n.a. n.a. — G-5d

0.43 199 A G-5e

0.35 185 A

Experimental Procedure for the Synthesis of G-7a

G-6a (590.0 mg, 2.49 mmol) is dissolved in dry THF (1.50 mL) and themixture is cooled to 0° C. LiAIH₄ (2 M in THF, 6.22 mL, 12.44 mmol, 5.00eq.) is added dropwise and the mixture is stirred in a closed vessel for1.5 h at 70° C. After complete conversion the mixture is diluted withTHF (15 mL), potassium sodium tartrate tetrahydrate is slowly added andthe mixture is stirred for 1.5 h at rt. The mixture is filtered, thefiltrate is concentrated and the crude product is used for the followingstep without purification.

The following intermediates G-7 (4 building bocks H—R⁵; table 12) areavailable in an analogous manner starting from the correspondingN-Boc-amino ketones G-6.

TABLE 12 # structure t_(ret) [min] [M + H]⁺ HPLC method G-7a

0.28 142 A G-7b

0.30 156 A G-7c

0.30 154 A

Experimental Procedure for the Synthesis of E-10a

To E-9a (500 mg, 2.71 mmol, 1.0 eq.) in acetone (11 mL) at 0° C. isadded a solution of piperazine-1-carboxylic acid tert-butyl ester (505mg, 2.71 mmol; 1.0 eq.) in acetone (6 mL). An aqueous solution of sodiumbicarbonate (225.00 mg, 2.12 mmol; 0.78 eq.) in water (5 mL) is addedand the reaction is stirred at 0° C. for 3 h. The reaction mixture isfiltered and the solid washed with water and dried to afford the desiredcompound E-10a (HPLC method A, t_(ret)=1.47 min, [M+H]⁺=334).

Experimental Procedure for the Synthesis of E-11a

E-10a (1.04 g, 3.11 mmol, 1.0 eq.),(S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (561.41 mg, 4.05 mmol, 1.3eq.) and DIPEA (808.47 mg, 6.22 mmol, 2.0 eq.) are dissolved inanhydrous THF (12 mL) and stirred at rt for 3 h, then at 40° C. for 1 h.The solvent is removed in vacuo and the residue is purified by normalphase chromatography (cyclohexane: EtOAc from 10:90→80:20) to affordE-11a (HPLC method A, t_(ret)=1.54 min, [M+H]⁺=427).

Experimental Procedure for the Synthesis of E-8a

E-11a (898 mg, 1.68 mmol, 1.0 eq.) and sodium cyanide (329.85 mg, 6.73mmol, 4.0 eq.) are dissolved in DMSO (5 mL) and stirred at 60° C. for 3h. The solvent is removed and the residue purified by reverse phasechromatography to afford the desired compound E-8a (H PLC method A,t_(ret)=1.53 min, [M+H]⁺=418)

Experimental Procedure for the Synthesis of E-8b

To a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (792 mg,6.13 mmol, 1.1 eq.) and DIPEA (1.94 mL, 11.15 mmol, 2 eq.) in DMSO (3mL) is slowly added a solution of E-1a (1000 mg, 97% purity, 5.58 mmol,1.0 eq.) in DMSO (3 mL). The mixture is stirred at rt for 30 min. Afterfull conversion of the starting materials is observed tert-butyl(R)-3-methylpiperazine-1-carboxylate (1.50 mg, 97% purity, 7.25 mmol,1.3 eq.) and DIPEA (0.97 mL, 5.58 mmol, 1 eq.) are added to the mixture.The mixture is stirred at 60° C. for 60 min and DIPEA (0.97 mL, 5.58mmol, 1 eq.) is added. The mixture is stirred at 70° C. for 50 min andat rt over night. After full conversion is observed the reaction isdiluted with water and DCM and the phases are separated. The aqueousphase is extracted with DCM (3×) and the organic phases are combined.The solvent is removed under vacuum to give the crude product E-8a. Thecrude product is dissolved in acetonitrile and water, filtered andpurified by basic reversed phase chromatography (gradient elution: 35%to 95% acetonitrile in water) to give the desired purified product E-8b.

The following intermediates E-8 (table 13) are available in an analogousmanner without isolation of the corresponding intermediates E-2. Thecrude product E-8 is purified by chromatography if necessary.

TABLE 13 # structure t_(ret) [min] [M + H]⁺ HPLC method E-8b

1.62 431 A E-8c

1.67 443 A

Experimental Procedure for the Synthesis of E-8d

To a solution of E-1a (600 mg, 3.21 mmol, 93% purity, 1.0 eq.) inanhydrous DMSO (6 mL) is added cesium fluoride (1.218 g, 8.02 mmol, 2.5eq.) and the resulting mixture is stirred at rt for 1 h until fullconversion of the staring material is observed. The resulting suspensionis filtered and the filtered solid is washed with anhydrous DMSO (2 mL).The filtrate (8 mL) is added to(S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (453 mg, 3.51 mmol, 1.1eq.) and DIPEA (1.085 mL, 6.38 mmol, 2 eq.) is added. The mixture isstirred at rt for 1 h. After full conversion of the starting materialsis observed a solution of tert-butyl piperazine-1-carboxylate (674 mg,3.51 mmol, 97% purity, 1.1.eq.) in anhydrous DMSO (3 mL) and DIPEA(1.085 mL, 6.38 mmol, 2 eq.) is added to the mixture. The mixture isstirred at rt for 30 min. After full conversion is observed the reactionis diluted with acetonitrile and water, filtered and purified by basicreversed phase chromatography (gradient elution: 30% to 98% acetonitrilein water) to give the desired product E-8d.

The following intermediates E-8 (table 14) are available in an analogousmanner without isolation of the corresponding intermediates E-5 and E-7,respectively. The crude product E-8 is purified by chromatography ifnecessary.

TABLE 14 # structure t_(ret) [min] [M + H]⁺ HPLC method E-8d

1.55 417 A E-8e

1.67 445 A E-8f

1.66 445 A

Experimental Procedure for the Synthesis of E-89 (Method A)

E-4f (50.0 mg, 0.148 mmol), G-5a (115 mg, 0.740 mmol, 5.0 eq.) and DIPEA(25.78 μL, 0.15 mmol, 1.0 eq.) are combined with dry NMP (10 μL) and themixture is stirred in a closed vessel for 1 h at 120° C. The product isisolated via basic reversed phase chromatography (gradient elution: 40%to 98% acetonitrile in water) yielding E-8g.

Intermediates E-8 marked “A” (table 15) are available in an analogousmanner. The crude product E-8 is purified by chromatography ifnecessary.

Experimental Procedure for the Synthesis of E-8h (Method B)

E-4e (400.0 mg, 1.24 mmol), N-methylpiperazine (352.1 mg, 3.48 mmol, 2.8eq.), sodium tert-butoxide (246.3 mg, 2.49 mmol, 2.0 eq.),2-(di-tert-butylphosphino)biphenyl (74.18 mg, 0.25 mmol, 0.20 eq.), andtris(dibenzylideneacetone)dipalladium(0) (56.9 mg, 0.062 mmol, 0.05 eq.)are combined in dry dioxane (2.50 mL) and the mixture is stirred for 1 hat 110° C. After complete conversion the mixture is concentrated,diluted with water, the product is extracted with DCM and the combinedorganic layers are dried, filtered, and concentrated. The crude productis purified via basic reversed phase chromatography (gradient elution:35% to 98% acetonitrile in water) yielding E-8h.

The intermediates E-8 marked “B” (table 15) are available in ananalogous manner. The crude product E-8 is purified by chromatography ifnecessary.

Experimental Procedure for the Synthesis of E-8i (Method C)

E-4b (1.00 g, 3.10 mmol), (S)-1,3-dimethylpiperazine (0.99 g, 8.67 mmol,2.80 eq.), tris(dibenzylideneacetone)dipalladium(0) (141.85 mg, 0.154mmol, 0.05 eq.), xantphos (184.80 mg, 0.31 mmol, 0.10 eq.), cesiumcarbonate (2.019 g, 6.196 mmol, 2.00 eq.) and dry dioxane (8.00 mL) arecombined and stirred in a closed vessel under argon atmosphere for 16 hat 110° C. After complete conversion brine is added to the mixture andthe product is extracted with DCM. The combined organic phases aredried, filtered and concentrated under reduced pressure. The crudeproduct is purified via basic reversed phase chromatography (gradientelution: 30% to 98% acetonitrile in water) yielding E-8i.

The intermediates E-8 marked “C” (table 15) are available in ananalogous manner. The crude product E-8 is purified by chromatography ifnecessary.

Experimental Procedure for the Synthesis of E-8j (Method D)

E-4g (3.035 g, 8.51 mmol), tert-butyl(S)-3-ethylpiperazine-1-carboxylate (3.645 g, 17.01 mmol, 2.00 eq.),tris(dibenzylideneacetone)dipalladium(0) (778.82 mg, 0.850 mmol, 0.10eq.), 1,3-bis(2,6-di-i-propylphenyl)imidazolium chloride (723.0 mg,1.701 mmol, 0.20 eq.), cesium carbonate (8.313 g, 25.514 mmol, 3.00 eq.)and dry dioxane (32.00 mL) are combined and stirred in a closed vesselunder argon atmosphere for 16 h at 110° C. After complete conversionbrine is added to the mixture and the product is extracted with DCM. Thecombined organic phases are dried, filtered and concentrated underreduced pressure. The crude product is purified via basic reversed phasechromatography (gradient elution: 30% to 98% acetonitrile in water)yielding E-8j.

Intermediates E-8 marked “D” (table 15) are available in an analogousmanner. The crude product E-8 is purified by chromatography ifnecessary.

Experimental Procedure for the Synthesis of E-8k (Method E)

E-4b (400 mg, 1.239 mmol), 1-(1-methylpiperidin-4-yl)piperazine (273.0mg, 1.49 mmol, 1.20 eq.), RuPhos Pd G3 (106.0 mg, 0.120 mmol, 0.10 eq.),potassium phosphate tribasic (553.0 mg, 2.605 mmol, 2.10 eq.) and drydioxane (3.10 mL) are combined and stirred in a closed vessel underargon atmosphere for 2 h at 85° C. After complete conversion the mixtureis diluted with DCM and filtered. The crude mixture is purified vianormal phase chromatography (DCM/MeOH/NH₃) yielding E-8k.

Intermediates E-8 marked “E” (table 15) are available in an analogousmanner. The crude product E-8 is purified by chromatography ifnecessary.

Experimental Procedure for the Synthesis of E-8I (Method F)

E-4b (100 mg, 0.31 mmol), pyridine-4-boronic acid (45.70 mg, 0.37 mmol,1.20 eq.), RuPhos Pd G3 (27.3 mg, 0.031 mmol, 0.10 eq.), potassiumphosphate tribasic (138.1 mg, 0.65 mmol, 2.10 eq.) and dry dioxane (0.9mL) are combined and stirred in a closed vessel under argon atmospherefor 1 h at 80° C. After complete conversion the mixture is concentrated.The crude product is purified via basic reversed phase chromatographyyielding E-8I.

Intermediates E-8 marked “F” (table 15) are available in an analogousmanner. The crude product E-8 is purified by chromatography ifnecessary.

Experimental Procedure for the Synthesis of E-8m (Method G)

To a mixture of DIPEA (736.3 μL, 4.23 mmol, 3 eq.) and E-4i (560 mg,1.41 mmol, 85% purity, 1 eq.) in DMSO (1 mL) is added(S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (922 mg, 5.64 mmol, 79%purity, 4.0 eq.) and the mixture is stirred at 100° C. for 16 h. Themixture is cooled to rt, diluted with acetonitrile and water, filteredand purified by acidic reversed phase chromatography (gradient elution:10% to 98% acetonitrile in water) to give the desired product E-8m.

Intermediates E-8 marked “G” (table 15) are available in an analogousmanner. The crude product E-8 is purified by chromatography ifnecessary.

Experimental Procedure for the Synthesis of E-8n (Method H)

A mixture of E-4k (1.50 g, 4.44 mmol, 1.0 eq.) and(S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (688 mg, 5.33 mmol, 1.2eq.) in THF (45 mL) is cooled to 0° C. Sodium tert-butoxide (854 mg,8.88 mmol, 2.0 eq.) is added at 0° C. to the mixture. The mixture isslowly warmed to rt and stirred for 2 h at rt. The reaction is quenchedby the addition of cold water and EtOAc. The phases are separated andthe aqueous layer is extracted with EtOAc. The combined organic layersare washed with brine solution and concentrated under vacuum. The crudeproduct is purified by normal phase chromatography (2% MeOH in DCM) togive the desired product E-8n.

Intermediates E-8 marked “H” (table 15) are available in an analogousmanner. The crude product E-8 is purified by chromatography ifnecessary.

Experimental Procedure for the Synthesis of E-80 (Method I)

A solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (312 mg,2.42 mmol, 1.7 eq.) in THF (3 mL) is cooled to 0° C. and sodium hydride(74 mg, 1.85 mmol, 1.3 eq.) is added portion wise over 10 min. To themixture is slowly added a solution of E-4I (500 mg, 1.42 mmol, 1.0 eq.)in THF (5 mL) and the mixture is stirred for 18 h. The reaction isquenched by the addition of saturated aqueous ammonium chloridesolution. The mixture is extracted with a mixture of DCM and MeOH (9:1).The phases are separated and the organic layer is concentrated undervacuum. The crude product is purified by normal phase chromatography (2%MeOH in DCM) to give the desired product E-8o.

The intermediates E-8 marked “I” (table 15) are available in ananalogous manner. The crude product E-8 is purified by chromatography ifnecessary.

Experimental Procedure for the Synthesis of E-8p (Method J)

To a mixture of E-4r (200 mg, 0.59 mmol, 1.0 eq.) and(S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (91.8 mg, 0.71 mmol, 1.2eq.) in acetonitrile (1.5 mL) is added trimethylamine (149.8 mg, 1.48mmol, 2.5 eq.). The mixture is stirred at 40° C. for 2 h. The mixture isstirred at 80° C. for 16 h. The solvent is removed under reducedpressure and the crude product is purified by normal phasechromatography (gradient elution: 0% to 90% MeOH in DCM+ammonia) to givethe desired product E-8p.

Intermediates E-8 marked “J” (table 15) are available in an analogousmanner. The crude product E-8 is purified by chromatography ifnecessary.

TABLE 15 # method structure t_(ret) [min] [M + H]⁺ HPLC method E-8g A

1.49 430 A E-8h B

0.71 386 B E-8i C

0.76 401 B E-8j D

1.65 535 A E-8k E

0.68 470 D E-8l F

0.54 366 F E-8m G

0.43 431 F E-8n H

n.a. n.a. — E-8o I

n.a. n.a. — E-8p J

0.46 431 F E-8q C

0.90 533 B E-8r C

0.82 413 B E-8s C

0.66 429 B E-8t D

1.55 473 A E-8u C

0.91 533 B E-8v B

1.23 387 A E-8w E

0.70 457 D E-8x E

0.77 472 D E-8y E

0.84 429 D E-8z E

0.73 456 D E-8aa E

0.50 455 F E-8ab G

n.a. n.a. — E-8ac A

1.64 486 A E-8ad A

1.61 474 A E-8ae A

0.83 472 B E-8af A

1.58 488 A E-8ag A

1.36 403 A E-8ah G

1.53 445 A E-8ai G

1.53 445 A E-8aj G

1.51 443 A E-8ak I

n.a. n.a. — E-8al J

0.75 443 G E-8am J

0.79 457 G E-8an J

0.50 455 F E-8ao G

n.a. n.a. — E-8ap G

1.50 405 A E-8aq G

1.42 417 A E-8ar B

0.70 387 B E-8as A

1.36 402 A E-8at G

1.30 376 A E-8au A

0.94 514 B E-8av A

0.73 430 B E-8aw A

0.77 442 B E-8ax A

0.78 442 B E-8ay A

1.53 456 A E-8az A

1.48 442 A E-8ba A

1.69 528 A E-8bb A

1.55 529 A E-8bc A

1.52 471 A E-8bd A

1.40 428 A E-8be A

1.55 440 A E-8bf A

1.51 442 A E-8bg A

0.73 401 B E-8bh A

0.80 415 B E-8bi A

0.74 401 B E-8bj A

0.65 387 B E-8bk A

n.a. n.a. — E-8bl A

n.a. n.a. — E-8bm C

1.41 416 A E-8bn I

0.73 402 B E-8bo A

1.39 402 A E-8bp G

0.76 401 B E-8bq G

1.24 401 A E-8br I

0.70 388 B E-8bs G

1.57 460 A E-8bt D

1.51 459 A E-8bu G

1.56 416 A E-8bv I

1.44 417 A E-8bw J

1.54 445 A E-8bx I

1.44 417 A E-8by J

1.58 417 A E-8bz G

1.32 413 A E-8ca G

1.36 416 A

Experimental Procedures for the Synthesis of Intermediates E-8cc

E-2b (3.94 g, 20.93 mmol, 4.0 eq.), tert-butyl piperazine-1-carboxylate(1.76 g, 5.23 mmol, 1.0 eq.), sodium tert-butoxide (2.01 g, 20.93 mmol,4.0 eq.), 2-(di-tert-butylphosphino)-biphenyl (624.45 mg, 0.21 mmol, 0.4eq.), tris-(dibenzylideneacton)-dipalladium (479.05 mg, 0.052 mmol, 0.1eq.) in dioxane (10 mL) are added to a sealed tube and shaken at 45° C.under nitrogen overnight. The reaction mixture is mixed with EtOAc andwater and extracted into EtOAc. The organic phase is dried overmagnesium sulfate and purified by normal phase chromatography on silicagel (DCM:MeOH from 100:0 to 80:20).

The following intermediates E-8 (table 16) are available in an analogousmanner. The crude product E-8 is purified by chromatography ifnecessary.

TABLE 16 # structure t_(ret) [min] [M + H]⁺ HPLC method E-8cc

1.28 375 A E-8cd

1.35 389 A E-8ce

1.43 401 A

Experimental Procedure for the Synthises of E-8cf (Method K)

To a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (1.335 g,8.16 mmol, 2.5 eq.) in DMF (50 mL) is added sodium hydride (60%dispersion in mineral oil, 652.8 mg, 16.32 mmol, 5.0 eq.) at rt. Themixture is stirred for 10 min at rt and E-6g (1.00 g, 3.26 mmol, 1.0eq.) is added. The mixture is stirred for 3 h at rt. The reaction isquenched by the addition of water and EtOAc. The phases are separatedand the aqueous phase is extracted with EtOAc. The organic layers arecombined, dried, filtered, and the solvent is removed under vacuum. Thecrude product is purified by basic reversed phase chromatography to giveE-8cf.

Intermediates E-8 marked “K” (table 17) are available in an analogousmanner. The crude product E-8 is purified by chromatography ifnecessary.

Experimental Procedure for the Synthesis of E-8cg (Method L)

To a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (52.6 mg,0.41 mmol, 5.0 eq.) in THF (2 mL) is added potassium tert-butoxide (45.6mg, 0.41 mmol, 5.0 eq.) at rt. The mixture is stirred for 30 min at rtand E-6b (25.0 mg, 0.081 mmol, 1.0 eq.) is added. The mixture is stirredfor 15 min at rt. The reaction is quenched by the addition of water andEtOAc. The phases are separated and the aqueous phase is extracted withEtOAc. The organic layers are combined and the solvent is removed undervacuum. The crude product is purified by acidic reversed phasechromatography to give E-8cg.

Intermediates E-8 marked “L” (table 17) are available in an analogousmanner. The crude product E-8 is purified by chromatography ifnecessary.

Experimental Procedure for the Synthesis of E-8ch (Method M)

E-6h (100.0 mg, 0.31 mmol, 1.0 eq.) and (S)-1,3-dimethylpiperazine (42.5mg, 0.37 mmol, 1.2 eq.) are dissolved in DMSO (1 mL) at rt and DIPEA(115.0 μL, 0.62 mmol, 2.0 eq.) is added and the mixture is stirred for 1h. The mixture is diluted with acetonitrile and water and purified byacidic reversed phase chromatography to give E-8ch.

Intermediates E-8 marked “M” (table 17) are available in an analogousmanner. The crude product E-8 is purified by chromatography ifnecessary.

TABLE 17 # method structure t_(ret) [min] [M + H]⁺ HPLC method E-8cf K

0.80 416 B E-8cg L

1.52 417 A E-8ch M

1.55 417 A E-8ci L

1.53 417 A E-8cj L

1.66 432 A E-8ck L

0.92 456 G E-8cl L

0.95 470 G E-8cm L

0.59 459 F

Experimental Procedure for the Synthesis of E-8cn

E-8j (2.404 g, 4.50 mmol) in DCM (41 mL) is treated with HCl (4 M indioxane, 8.33 mL, 33.31 mmol, 7.4 eq.) and the mixture is stirred for 5h at rt. After complete conversion, the mixture is concentrated and thecrude product is purified via basic reversed phase chromatography(gradient elution: 25% to 100% acetonitrile in water) yielding E-8cn.

The following intermediates E-8 (table 18) are available in an analogousmanner. The crude product E-8 is purified by chromatography ifnecessary.

TABLE 18 # structure t_(ret) [min] [M + H]⁺ HPLC method E-8cn

1.35 435 A E-8co

0.66 433 B E-8cp

0.65 433 B

Experimental Procedure for the Synthesis of E-8cg

E-8cn (231 mg, 0.532 mmol) in DCM (10.72 mL) is treated withformaldehyde (37% in water, 79.89 μL, 1.06 mmol, 2.0 eq.), acetic acid(304.0 μL, 5.32 mmol, 10.0 eq.), and a small amount of molecular sievesand the mixture is stirred for 15 min. Sodium triacetoxyborohydride(232.3 mg, 1.06 mmol, 2.0 eq.) is added and the mixture ist stirred for2 h at rt. After complete conversion the mixture is diluted with brineand the product is extracted with DCM. The combined organic extracts aredried, filtered and concentrated and the crude product is purified viabasic reversed phase chromatography (gradient elution: 35% to 98%acetonitrile in water) yielding E-8cq.

The following intermediates E-8 (table 19) are available in an analogousmanner. The crude product E-8 is purified by chromatography ifnecessary.

TABLE 19 # structure t_(ret) [min] [M + H]⁺ HPLC method E-8cq

1.47 449 A E-8cr

1.43 447 A E-8cs

1.34 447 A

Experimental Procedure for the Synthesis of E-14a

E-8i (240.0 mg, 0.60 mmol), hydroxylamine hydrochloride (110.48 mg, 1.56mmol, 2.60 eq.) and sodium carbonate (81.79 mg 0.78 mmol, 1.30 eq.) aredissolved in dry EtOH (3.90 mL) and the mixture is stirred at 85° C. for1 h. After complete conversion the mixture is concentrated under reducedpressure to afford E-14a which is used for the next step without furtherpurification.

The following intermediates E-14 (table 20) are available in ananalogous manner using different nitriles E-8. The crude product E-14 ispurified by chromatography if necessary.

TABLE 20 # structure t_(ret) [min] [M + H]⁺ HPLC method E-14a

0.60 434 B E-14b

1.25 463 A E-14c

0.50 419 B E-14d

1.27 482 A E-14e

1.21 480 A E-14f

0.66 446 B E-14g

0.50 462 B E-14h

1.33 506 A E-14i

0.56 480 B E-14j

1.30 449 A E-14k

0.52 420 D E-14l

0.53 503 D E-14m

0.27 490 F E-14n

0.61 505 D E-14o

0.67 462 D E-14p

0.51 489 D E-14q

0.38 399 F E-14r

0.30 488 E E-14s

n.a. n.a. — E-14t

0.95 519 B E-14u

0.80 508 B E-14v

0.70 505 B E-14w

1.38 521 A E-14x

0.58 436 B E-14y

0.34 464 F E-14z

1.31 478 A E-14aa

0.63 464 G E-14ab

1.29 478 A E-14ac

1.32 478 A E-14ad

1.33 476 A E-14ae

0.58 478 G E-14af

0.63 476 G E-14ag

0.67 490 G E-14ah

1.33 476 A E-14ai

0.63 478 G E-14aj

0.64 422 G E-14ak

0.56 438 F E-14al

1.41 476 A E-14am

0.65 450 G E-14an

0.36 450 F E-14ao

0.72 489 G E-14ap

0.76 503 G E-14aq

0.43 450 F E-14ar

0.80 492 B E-14as

0.54 420 D E-14at

0.59 435 B E-14au

0.57 409 B E-14av

0.53 408 B E-14aw

0.82 547 B E-14ax

0.60 463 B E-14ay

0.63 475 B E-14az

0.62 475 B E-14ba

0.64 489 B E-14bb

0.60 475 B E-14bc

0.80 561 B E-14bd

0.69 562 B E-14be

0.66 504 B E-14bf

0.31 461 C E-14bg

1.33 473 A E-14bh

 0.634 475 B E-14bi

0.57 434 B E-14bj

0.62 448 B E-14bk

0.57 434 B E-14bl

0.49 420 B E-14bm

n.a. n.a. — E-14bn

n.a. n.a. — E-14bo

0.65 449 B E-14bp

0.56 435 B E-14bq

0.59 435 B E-14br

0.58 434 B E-14bs

0.54 434 B E-14bt

0.56 421 B E-14bu

0.70 493 B E-14bv

0.65 492 B E-14bw

1.44 449 A E-14bx

0.57 450 G E-14by

0.68 478 B E-14bz

0.62 450 B E-14ca

0.57 450 G E-14cb

0.59 451 B E-14cc

0.55 422 B E-14cd

0.58 446 B E-14ce

0.57 434 B E-14cf

0.62 449 B E-14cg

1.04 393 A

Experimental Procedure for the Synthesis of E-15a

To a solution of E-1e (10.00 g, 45.99 mmol) in TEA (19.20 mL, 137.96mmol, 3.0 eq.) and EtOH (100.0 mL) is added hydroxyl amine hydrochloride(6.39 g, 91.98 mmol, 2.0 eq.) and the mixture is stirred at rt for 2 h.After complete conversion the solvent is evaporated under reducedpressure and the residue is partitioned between EtOAc and 10% Na₂CO₃solution. The organic layer is collected and the aqueous layer isfurther extracted with EtOAc. The combined organic layers are washedwith brine, dried, filtered and concentrated under reduced pressure toyield E-15a which is used for the next step without furtherpurification.

Experimental Procedure for the Synthesis of E-16a

To a solution of E-4b (1.00 g, 3.10 mmol) in THF (0.50 mL) is addedhydroxyl amine (50% in water, 363 μL, 2.5 eq.) at rt. The mixture isstirred for 3 h at rt. After complete conversion the mixture isconcentrated under reduced pressure to afford E-16a which is used forthe next step without further purification.

The following intermediates E-16 (table 21) are available in ananalogous manner using different nitriles E-4. The crude product E-16 ispurified by chromatography if necessary.

TABLE 21 # structure t_(ret) [min] [M + H]⁺ HPLC method E-16a

0.61 356 B E-16b

n.a. n.a. — E-16c

n.a. n.a. — E-16d

n.a. n.a. —

Experimental Procedure for the Synthesis of B-1a

To a stirred solution of E-15a (6.75 g, 26.95 mmol) and A-5a (7.00 g,29.64 mmol, 1.1 eq.) in DMF (70 mL) DIPEA (13.99 mL, 80.85 mmol, 3.0eq.) is added at rt. The mixture is cooled to 0° C. andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(21.04 g, 40.42 mmol, 1.5 eq.) is added. The mixture is allowed to reachrt and stirred for 16 h. After complete conversion the mixture isdiluted with EtOAc and washed with water and brine, dried, filtered andconcentrated under reduced pressure. The crude product is purified bycolumn chromatography (hexane/EtOAc) and afterwards titurated using DCMyielding B-1a.

The reaction here can also be performed using enantiopure startingmaterial A-5 yielding enantiopure products B-1.

Experimental Procedure for the Synthesis of B-2a

To a stirred solution of B-1a (2.50 g, 5.33 mmol) in THF (250 mL) isadded benzyltrimethylammonium hydroxide solution (40 wt. % in MeOH,1.962 g; 11.73 mmol, 2.2 eq.) at 0° C. and the mixture is allowed tostir for 6 min at rt. The reaction is quenched by adding 25 mL of waterand 25 mL of EtOAc. The layers are separated and the organic phase iswashed with water, dried, filtered, and concentrated under reducedpressure. The crude product is purified by column chromatography(hexane/EtOAc) yielding B-2a.

Experimental Procedure for the Synthesis of B-3a

The reaction is carried out under argon atmosphere. To a stirred mixtureof zinc powder (497.22 mg, 7.60 mmol, 8.0 eq.) and dry DMA (1.24 mL) isadded 160 μL of a 7:5 (v/v) mixture of chlorotrimethylsilane (0.730 mL)and 1,2-dibromoethane (0.520 mL) dropwise over a period of 10 min at rtand the resulting mixture is stirred for additional 15 min at rt. Asolution of tert-butyl 4-iodopiperidine-1-carboxylate (1.941 g, 6.05mmol, 13.2 eq.) in dry DMA (3.08 mL) is added portionwise while keepingthe temperature below 35° C. The resulting mixture is stirred foradditional 30 min while cooling down to rt.

In a second flask dry DMA (1.4 mL) is added to a mixture of B-2a (200.0mg, 0.44 mmol), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)dichloride, DCM (16.82 mg, 0.02 mmol, 0.09 eq.), and copper(I)iodide(9.61 mg, 0.05 mmol, 0.23 eq.). The mixture is degassed and 1.14 mL ofthe previously prepared piperidyl zinc iodide solution (21% of thesolution prepared according to the procedure above) are added through a0.45 μm syringe filter. The resulting solution is again degassed andthen stirred for 1 h at 80° C. After complete conversion DCM, water, andsaturated ammonium chloride solution is added, the layers are separatedand the aqueous layer is extracted with DCM. The organic layers arecombined, dried, filtered and concentrated under reduced pressure andthe crude product is purified via basic reversed phase chromatography(gradient elution: 50% to 98% acetonitrile in water) yielding B-3a (HPLCmethod B; t_(ret)=0.88 min; [M+H]⁺=499).

Experimental Procedure for the Synthesis of B-4a

B-3a (200.0 mg, 0.360 mmol) is treated with 1-methylpiperazine (799.30μL, 7.21 mmol, 20 eq.) and DIPEA (92.99 μL, 0.54 mmol, 1.5 eq.) andstirred for 16 h at 80° C. in a closed vessel. After completeconversion, DCM, water, and brine are added, the layers are separatedand the aqueous layer is extracted with DCM. The organic layers arecombined, dried, filtered and concentrated under reduced pressureyielding B-4a which is used for the following step without furtherpurification.

The following intermediates B-4 (table 22) are available in an analogousmanner using different piperazine analogues B-3. The crude product B-4is purified by chromatography if necessary.

TABLE 22 # structure t_(ret) [min] [M + H]⁺ HPLC method B-4a

0.84 619 B B-4b

0.98 673 B

Experimental Procedure for the Synthesis of B-4c

B-3b (100.0 mg, 0.18 mmol) is treated with 1-pyrrolidin-3-yl-piperidine(277.39 mg, 1.80 mmol, 10 eq.) and DIPEA (154.7 μL, 0.90 mmol, 5.0 eq.)and stirred for 16 h at 100° C. in a closed vessel. After completeconversion, DCM, water, and brine are added, the layers are separatedand the aqueous layer is extracted with DCM. The organic layers arecombined, dried, filtered and concentrated under reduced pressureyielding B-4c which is used for the following step without furtherpurification.

The following intermediates B-4 (table 23) are available in an analogousmanner using different intermediates B-3. The crude product B-4 ispurified by chromatography if necessary.

TABLE 23 # structure t_(ret) [min] [M + H]⁺ HPLC method B-4c

0.90 674 B B-4d

1.53 648 A B-4e

0.92 674 B B-4f

0.87 648 B B-4g

1.67 689 A B-4h

0.78 656 C B-4i

0.88 686 B B-4j

1.37 620 A B-4k

n.a. n.a. — B-4l

0.89 660 B B-4m

0.93 674 B B-4n

1.45 652 A B-4o

1.56 677 (M − tBu) A B-4p

1.76 719 A B-4q

0.89 660 B B-4r

0.93 674 B B-4s

0.83 646 B B-4t

0.87 660 B B-4u

1.56 662 A B-4v

1.50 648 A B-4w

1.49 646 A B-4x

0.79 623 B

Experimental Procedure for the Synthesis of B-5a

B-4a (111.5 mg, 0.18 mmol) in DCM (2.00 mL) is treated with HCl (4 M indioxane, 900.8 μL, 3.60 mmol, 20.0 eq.) and the mixture is stirred for 1h at rt. After complete conversion, the mixture is concentrated and thecrude product is purified via basic reversed phase chromatography(gradient elution: 15% to 90% acetonitrile in water) yielding B-5a.

The following intermediates B-5 (table 24) are available in an analogousmanner using different piperazine analogues B-4. The crude product B-5is purified by chromatography if necessary.

TABLE 24 # structure t_(ret) [min] [M + H]⁺ HPLC method B-5a

0.52 519 B B-5b

0.74 573 B

Scheme 5:

Experimental Procedure for the Synthesis of B-6a

To a solution of B-2b (250.0 mg, 0.56 mmol) in DMF (3.5 mL) is addedN,N-dimethylformamide dimethyl acetal (674.4 μL, 5.55 mmol, 10.0 eq.)and the reaction mixture is stirred at rt for 16 h. After completeconversion the product is isolated via basic reversed phasechromatography (gradient elution: 50% to 98% acetonitrile in water)yielding B-6a (HPLC method A; t_(ret)=1.61 min; [M+H]⁺=505).

Experimental Procedure for the Synthesis of B-7a

Procedure carried out in a glovebox under nitrogen atmosphere. B-6a(1.00 g, 1.785 mmol), (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol(369.0 mg, 2.86 mmol, 1.6 eq.), sodium tert-butoxide (257.3 mg, 2.68mmol, 1.5 eq.), and [BrettPhos Pd(crotyl)]OTf (151.4 mg, 0.18 mmol, 0.1eq.) are combined, dry dioxane (15.0 mL) is added and the mixture isstirred in a closed vessel for 16 h at rt. After complete conversion,the mixture is poured into water, the pH is set to 10 by addition of 8 NNaOH, the product is extracted with DCM and the combined organic layersare dried, filtered and concentrated. The crude product is purified viabasic reversed phase chromatography (gradient elution: 60% to 98%acetonitrile in water) yielding B-7a (HPLC method A; t_(ret)=1.74 min;[M+H]⁺=598).

Experimental Procedure for the Synthesis of B-8a

Procedure carried out in a glovebox under nitrogen atmosphere. B-7a(135.0 mg, 0.23 mmol), tert-butyl 3-hydroxyazetidine-1-carboxylate (78.1mg, 0.45 mmol, 2.0 equiv.), potassium phosphate (143.6 mg, 0.68 mmol,3.0 eq.), palladium(II) acetate (5.1 mg, 0.023 mmol, 0.1 eq.), and5-[di(1-adamantyl)phosphino]-1′,3′,5′-triphenyl-1′H-[1,4]bipyrazole(29.9 mg, 0.045 mmol, 0.2 eq.) are combined, dry toluene (2.7 mL) isadded and the mixture is stirred in a closed vessel for 16 h at 90° C.After complete conversion, the mixture is poured into water, the productis extracted with DCM and the combined organic layers are dried,filtered and concentrated. The crude product is purified via basicreversed phase chromatography (gradient elution: 5% to 98% acetonitrilein water) yielding B-8a.

The following intermediates B-8 (table 25) are available in an analogousmanner using different alcohols. The crude product B-8 is purified bychromatography if necessary.

TABLE 25 # structure t_(ret) [min] [M + H]⁺ HPLC method B-8a

1.70 691 A B-8b

n.a. n.a. —

Experimental Procedure for the Synthesis of B-5c

B-8a (112.2 mg, 0.16 mmol) is dissolved in EtOH (2.75 mL) and treatedwith conc. HCl (37% in water, 94.1 μL, 1.137 mmol, 7.0 eq.). The mixtureis stirred for 1 h at 100° C. and after complete conversion the mixtureis concentrated and the crude product is purified via basic reversedphase chromatography (gradient elution: 15% to 98% acetonitrile inwater) yielding B-5c.

The following intermediates B-5 (table 26) are available in an analogousmanner using different analogues B-8. The crude product B-5 is purifiedby chromatography if necessary.

TABLE 26 # structure t_(ret) [min] [M + H]⁺ HPLC method B-5c

1.34 536 A B-5d

0.64 564 B

Experimental Procedure for the Synthesis of B-9a

A-5a (67.09 mg, 0.28 mmol, 0.90 eq.) in DMSO (1.0 mL) is treated withHATU (125.9 mg, 0.32 mmol, 1.05 eq.) and TEA (89.2 μL, 0.62 mmol, 2.0eq.) and the mixture is stirred for 20 min at rt. Then E-16a (110.0 mg,0.31 mmol, 1.0 eq.) is added and the mixture is stirred for 2 h at rt.The mixture is poured into water and the precipitate is collected,washed with water, and dried, yielding B-9a which is used for the nextstep without further purification.

The reaction can also be performed using enantiopure starting materialA-5 yielding a single stereoisomer of product B-9.

The following intermediates B-9 (table 27) are available in an analogousmanner using different intermediates E-16 and acids A5. The crudeproduct B-9 is purified by chromatography if necessary.

TABLE 27 # structure t_(ret) [min] [M + H]⁺ HPLC method B-9a

n.a. n.a. — B-9b

0.83 588 B B-9c

1.48 573 A B-9d

0.75 531 G B-9e

0.85 547 G B-9f

0.81 533 G B-9g

n.a. n.a. — B-9h

0.83 588 B B-9i

0.76 592 B B-9j

0.76 592 B B-9k

1.42 572 A B-9l

n.a. n.a. —

Experimental Procedure for the Synthesis of B-3b

To a stirred solution of B-9a (180 mg, 0.31 mmol) in THF (1.0 mL) isadded tetrabutylammonium hydroxide solution (40% in water, 0.152 mL,0.23 mmol, 0.75 eq.) dropwise and the mixture is stirred for 16 h at rt.After full conversion the mixture is concentrated under reduced pressureand the crude product is purified via basic reversed phasechromatography (gradient elution: 30% to 98% acetonitrile in water)yielding B-3b.

The following intermediates B-3 (table 28) are available in an analogousmanner using different intermediates B-9. The crude product B-3 ispurified by chromatography if necessary.

TABLE 28 # structure t_(ret) [min] [M + H]⁺ HPLC method B-3b

1.46 556 A B-3c

0.87 570 B B-3d

1.63 612 A B-3e

0.78 569 G B-3f

0.88 585 G B-3g

0.84 571 G B-3h

n.a. n.a. — B-3i

0.87 570 B B-3j

0.78 576 B

Experimental Procedure for the Synthesis of B-10a

Performed in an analogous manner to the preparation of B-6 from B-2(see, e.g., procedure B-6a→B-2a).

The following intermediates B-10 (table 29) are available in ananalogous manner starting from different intermediates B-3. The crudeproduct B-10 is purified by chromatography if necessary.

TABLE 29 # structure t_(ret) [min] [M + H]⁺ HPLC method B-10a

1.54 599 A B-10b

0.95 640 G B-10c

0.84 624 G B-10d

0.90 626 G

Experimental Procedure for the Synthesis of B-8c

Procedure carried out in a glovebox under nitrogen atmosphere. B-10a(25.0 mg, 0.041 mmol), (1S)-1-[(2S)-1-methylpyrrolidin-2-yl]propan-1-ol(11.70 mg, 0.08 mmol, 2.0 eq.), sodium tert-butoxide (5.89 mg, 0.06mmol, 2.0 eq.) and BrettPhos Pd(crotyl)OTf (3.46 mg, 0.004 mmol, 0.1eq.) are combined. Degassed dioxane (0.5 mL) is added and the mixture isstirred in a closed vessel for 16 h at 60° C. under an inert atmosphere.The reaction mixture is filtered and the crude product is purified viaacidic reversed phase chromatography (gradient elution: 30% to 98%acetonitrile in water) yielding B-8c.

The following intermediates B-8 (table 30) are available in an analogousmanner starting from different intermediates B-10. The crude product B-8is purified by chromatography if necessary.

TABLE 30 # structure t_(ret) [min] [M + H]⁺ HPLC method B-8c

1.76 719 A B-8d

0.89 717 B B-8e

0.91 731 B B-8f

0.84 729 B B-8g

1.65 703 A B-8h

0.80 717 G B-8i

1.34 564 A B-8j

1.72 705 A B-8k

0.92 733 G B-8l

0.82 711 G B-8m

0.88 719 G B-8n

0.61 734 F B-8o

1.71 717 A B-8p

1.65 691 A B-8q

1.71 717 A B-8r

1.58 677 A B-8s

1.60 703 A B-8t

1.57 662 A

Experimental Procedure for the Synthesis of B-5e

B-8c (140.0 mg, 0.195 mmol) is dissolved in EtOH (3 mL) and concentratedaqueous HCl (134 mg, 1.36 mmol) is added. The mixture is stirred for 2 hat 100° C. under an inert atmosphere. The reaction mixture isconcentrated in vacuo and the crude product is purified via basicreversed phase chromatography (gradient elution: 30% to 90% acetonitrilein water) yielding B-5e.

The following intermediates B-5 (table 31) are available in an analogousmanner using different intermediates B-8. The crude product B-5 ispurified by chromatography if necessary.

TABLE 31 # structure t_(ret) [min] [M + H]⁺ HPLC method B-5e

1.20 550 A B-5f

1.20 550 A B-5g

1.25 562 A B-5h

0.55 576 B B-5i

0.54 574 B

Experimental Procedure for the Synthesis of B-11a

A-5a (454.0 mg, 1.91 mmol, 1.0 eq.) in DMF (11.8 mL) is treated withHATU (724.5 mg, 1.91 mmol, 1.0 eq.) and DIPEA (0.923 mL, 5.72 mmol, 3.0eq.) and the mixture is stirred for 20 min at rt. Then E-14a (874.8 mg,1.48 mmol, 0.78 eq.) is added and the mixture is stirred for 16 h at rt.The crude mixture is purified via basic reversed phase chromatography(gradient elution: 30% to 98% acetonitrile in water) yielding B-11a.

The reaction can also be performed using enantiopure starting materialA-5 yielding a single stereoisomer of product B-11.

The following intermediates B-11 (table 32) are available in ananalogous manner using different intermediates E-14 and acids A-5. Thecrude product B-11 is purified by chromatography if necessary.

TABLE 32 # structure t_(ret) [min] [M + H]⁺ HPLC method B-11a

0.79 652 B B-11b

1.53 681 A B-11c

0.69 637 B B-11d

1.51 700 A B-11e

1.47 698 A B-11f

0.84 664 B B-11g

0.72 680 B B-11h

1.56 724 A B-11i

1.42 698 A B-11j

0.82 667 B B-11k

0.71 624 D B-11l

0.71 721 D B-11m

0.75 708 G B-11n

0.80 723 D B-11o

0.86 680 D B-11p

0.70 707 D B-11q

0.65 617 F B-11r

0.77 706 G B-11s

n.a. n.a. — B-11t

1.66 737 A B-11u

0.89 725 B B-11v

0.86 723 B B-11w

1.60 739 A B-11x

0.77 654 B B-11y

0.73 682 G B-11z

0.83 708 G B-11aa

0.82 682 G B-11ab

1.58 696 A B-11ac

1.58 696 A B-11ad

1.65 694 A B-11ae

0.76 696? G B-11af

0.56 562 G B-11ag

0.83 708 G B-11ah

1.65 694 A B-11ai

0.81 696 G B-11aj

0.81 640 G B-11ak

0.76 656 G B-11al

1.59 694 A B-11am

0.60 668 F B-11an

0.57 668 F B-11ao

0.93 707 G B-11ap

0.92 721 G B-11aq

0.84 668 D B-11ar

1.72 710 A B-11as

0.76 638 B B-11at

n.a. n.a. — B-11au

0.76 627 B B-11av

1.29 626 A B-11aw

0.98 765 B B-11ax

1.51 681 A B-11ay

1.55 693 A B-11az

0.81 693 B B-11ba

1.58 707 A B-11bb

1.58 693 A B-11bc

1.70 n.a. A B-11bd

1.57 780 A B-11be

1.92 722 A B-11bf

1.49 679 A B-11bg

1.60 691 A B-11bh

1.58 693 A B-11bi

1.45 666 A B-11bj

0.83 666 B B-11bk

0.78 652 B B-11bl

0.72 638 B B-11bm

n.a. n.a. — B-11bn

n.a. n.a. — B-11bo

1.48 667 A B-11bp

0.76 653 B B-11bq

0.84 667 B B-11br

0.79 652 B B-11bs

0.75 652 B B-11bt

1.39 639 A B-11bu

1.59 711 A B-11bv

1.55 710 A B-11bw

1.60 667 A B-11bx

0.78 654 B B-11by

1.62 696 A B-11bz

0.78 654 B B-11ca

1.56 668 A B-11cb

1.49 669 A B-11cc

1.35 640 A B-11cd

1.39 664 A B-11ce

1.37 652 A B-11cf

0.81 667 B B-11cg

1.29 626 A

Experimental Procedure for the Synthesis of B-4y

To a stirred solution of B-11a (1.570 g, 1.45 mmol) in THF (16.0 mL) isadded tetrabutylammonium fluoride solution (1 M in THF, 2.168 mL, 2.17mmol, 1.50 eq.) dropwise and the mixture is stirred for 16 h at rt.After full conversion the mixture is filtered, concentrated underreduced pressure and the crude product is purified via basic reversedphase chromatography (gradient elution: 40% to 98% acetonitrile inwater) yielding B-4y.

The following intermediates B-4 (table 33) are available in an analogousmanner using different intermediates B-11. The crude product B-4 ispurified by chromatography if necessary.

TABLE 33 # structure t_(ret) [min] [M + H]⁺ HPLC method B-4y

0.84 634 B B-4z

1.60 663 A B-4aa

0.83 619 B B-4ab

1.59 682 A B-4ac

1.53 680 A B-4ad

0.87 646 B B-4ae

0.76 662 B B-4af

0.89 607 B B-4ag

0.79 680 B B-4ah

1.76 649 A B-4ai

0.74 606 D B-4aj

0.76 703 D B-4ak

0.80 690 D B-4al

0.86 705 D B-4am

0.90 662 D B-4an

0.84 689 D B-4ao

0.78 599 D B-4ap

0.83 688 G B-4aq

n.a. n.a. — B-4ar

n.a. n.a. — B-4as

0.99 708 B B-4at

1.63 705 A B-4au

n.a. n.a. — B-4av

0.79 636 B B-4aw

1.52 664 A B-4ax

1.61 678 A B-4ay

1.65 664 A B-4az

1.66 678 A B-4ba

1.59 678 A B-4bb

1.63 676 A B-4bc

0.77 678 G B-4bd

0.83 676 G B-4be

0.85 690 G B-4bf

1.63 676 A B-4bg

0.84 678 G B-4bh

1.57 662 A B-4bi

1.60 622 A B-4bj

0.83 638 G B-4bk

1.68 686 A B-4bl

1.58 703 A B-4bm

0.66 650 F B-4bn

1.63 650 A B-4bo

0.95 643 G B-4bp

1.55 641 A B-4bq

0.97 648 G B-4br

0.95 650 G B-4bs

1.00 692 G B-4bt

1.37 620 A B-4bu

1.50 635 A B-4bv

0.80 609 B B-4bw

1.47 608 A B-4bx

0.98 747 B B-4by

0.83 663 B B-4bz

1.59 675 A B-4ca

0.86 675 B B-4cb

1.65 689 A B-4cc

1.61 675 A B-4cd

1.72 n.a. A B-4ce

1.59 762 A B-4cf

1.63 704 A B-4cg

1.56 661 A B-4ch

1.65 673 A B-4ci

1.64 675 A B-4cj

0.87 648 B B-4ck

0.87 n.a. B B-4cl

0.87 634 B B-4cm

1.36 620 A B-4cn

n.a. n.a. — B-4co

n.a. n.a. — B-4cp

1.57 649 A B-4cq

n.a. n.a. — B-4cr

0.81 635 B B-4cs

0.90 649 B B-4ct

0.86 634 B B-4cu

0.77 634 B B-4cv

1.48 621 A B-4cw

1.65 693 A B-4cx

1.62 692 A B-4cy

1.67 649 A B-4cz

0.82 636 B B-4da

1.67 678 A B-4db

0.82 636 B B-4dc

1.63 650 A B-4dd

1.59 651 A B-4de

1.59 622 A B-4df

1.44 646 A B-4dg

1.53 634 A B-4dh

1.51 649 A

Experimental Procedure for the Synthesis of B-5j

B-4cn (400 mg, 0.50 mmol, 1 eq.) is dissolved in MeOH, then hydrogenatedat 50° C. using an H-Cube apparatus employing a palladium hydroxidecartridge. The solvent is removed in vacuo and the residue purifiedusing reverse phase chromatography to obtain B-5j (H PLC method A;t_(ret)=1.34 min; [M+H]⁺=606).

Experimental Procedure for the Boc and Cbz Deprotection of BuildingBlocks B-4 (B-4→B-5)

The following intermediates B-5 (table 34) can be obtained by Bocdeprotection or Cbz deprotection of building blocks B-4 in analogy to asdescribed herein (see B-4a→B-5a and B-4cn→B-5e).

TABLE 34 # structure t_(ret) [min] [M + H]⁺ HPLC method B-5k

1.49 563 A B-5l

1.10 519 A B-5m

0.76 602 B B-5n

0.69 586 B B-5o

0.73 588 B B-5p

0.59 534 B B-5q

0.59 534 B B-5r

1.29 548 A B-5s

1.17 546 A B-5t

0.63 546 B B-5u

1.09 562 A B-5v

1.31 606 A B-5w

0.61 560 B B-5x

0.63 562 B B-5y

0.64 574 B B-5z

0.60 560 B B-5aa

1.41 546 A B-5ab

0.59 549 B B-5ac

1.10 506 A B-5ad

1.74 603 A B-5ae

1.13 590 A B-5af

1.17 605 A B-5ag

0.66 562 D B-5ah

0.60 589 D B-5ai

0.35 499 F B-5aj

0.38 588 E B-5ak

0.36 590 E B-5al

0.59 574 B B-5am

0.62 588 B B-5an

0.62 592 B B-5ao

0.62 592 B B-5ap

0.61 592 B B-5aq

1.38 619 A B-5ar

1.41 607 A B-5as

1.29 605 A B-5at

1.39 621 A B-5au

0.54 536 B B-5ar

1.38 564 A B-5av

1.27 578 A B-5aw

1.30 564 A B-5ax

1.86 578 A B-5ay

1.22 578 A B-5az

1.26 576 A B-5ba

0.59 578 G B-5bb

1.28 576 A B-5bc

0.60 590 G B-5bd

1.25 564 A B-5be

1.28 578 A B-5bf

0,59 564 B B-5bg

0.63 578 B B-5bh

0.54 562 B B-5bi

0.26 579 F B-5bj

0.60 562 G B-5bk

0.51 536 G B-5bl

0.51 536 G B-5bm

0.50 562 G B-5bn

1.21 548 A B-5bo

0.55 562 G B-5bp

1.21 522 A B-5bq

1.14 522 A B-5br

0.52 548 G B-5bs

0.61 538 G B-5bt

1.30 576 A B-5bu

1.49 603 A B-5bv

1.40 550 A B-5bw

1.04 550 A B-5bx

0.69 589 G B-5by

0.73 603 G B-5bz

0.65 550 G B-5ca

0.37 592 F B-5cb

1.06 520 A B-5cc

1.21 535 A B-5cd

1.02 509 A B-5ce

1.14 508 A B-5cf

0.683 647 B B-5cg

0.675 563 B B-5ch

1.51 575 A B-5ci

2.57 575 A B-5cj

0.61 589 B B-5ck

1.20 575 A B-5cl

1.39 n.a. A B-5cm

1.32 n.a. A B-5cn

1.40 604 A B-5co

1.34 561 A B-5cp

0.72 574 B B-5cq

n.a. n.a. A B-5cr

0.64 548 B B-5cs

1.25 548 A B-5ct

0.72 574 B B-5cu

0.64 548 B B-5cv

1.17 534 A B-5cw

1.15 520 A B-5cx

1.15 548 A B-5cy

1.54 589 A B-5cz

0.59 521 B B-5da

0.57 556 B B-5db

0.55 549 A B-5dc

1.32 586 A B-5dd

1.06 520 A B-5de

0.56 521 B B-5df

0.57 535 B B-5dg

1.16 534 A B-5dh

0.61 549 B B-5di

1.25 560 A B-5dj

0.68 574 B B-5dk

0.58 534 B B-5dl

1.18 534 A B-5dm

1.15 552 A B-5dn

1.23 521 A B-5do

0.54 523 B B-5dp

1.32 593 A B-5dq

1.35 592 A B-5dr

1.54 549 A B-5ds

1.13 536 A B-5dt

1.31 578 A B-5du

1.13 536 A B-5dv

1.18 633 A B-5dw

1.25 550 A B-5dx

1.34 564 A B-5dy

0.62 564 B B-5dz

1.23 551 A B-5ea

1.21 535 A B-5eb

1.21 535 A B-5ec

1.75 522 A B-5ed

1.10 546 A B-5ef

1.19 534 A B-5eg

1.43 549 A B-5eh

1.25 560 A B-5ei

0.68 574 B B-5ej

0.60 546 B B-5ek

0.62 560 B B-5el

1.29 562 A B-5em

1.38 541 A B-5en

1.24 548 A B-5eo

1.22 546 A B-5ep

0.69 624 B

Synthesis of Final Compounds (1) According to the Invention

Experimental Procedure for the Synthesis of La-1

B5-a (29.5 mg, 0.057 mmol), TEA (23.7 μL, 0.171 mmol, 3.0 eq.), and DMSO(900.0 μL) are dissolved in DCM (1.0 mL). Acryloyl chloride (5.5 μL,0.068 mmol, 1.2 eq.) dissolved in DCM (1 mL) is added dropwise over aperiod of 10 min and the mixture is stirred for 30 min at rt. Additionalacryloyl chloride (3.2 μL, 0.04 mmol, 0.7 eq.) dissolved in DCM (0.2 mL)is added dropwise and the mixture is stirred for additional 30 min.After complete conversion, the mixture is concentrated and the crudeproduct is purified via acidic reversed phase chromatography (gradientelution: 5% to 60% acetonitrile in water) yielding Ia-1.

The following compounds (1) according to the invention of sub-genus Ia(table 35) are available in an analogous manner using differentanalogues B-5. The crude product Ia is purified by chromatography ifnecessary.

TABLE 35 IC₅₀ t_(ret) HPLC G12C::SOS1 # structure [min] [M + H]⁺ method[nM] Ia-1

1.23 573 A 123 Ia-2

1.41 627 A 336

Experimental Procedure for the Synthesis of Ia-3

A solution of acryloyl chloride (1 M in acetone, 336.0 μL, 0.34 mmol,3.0 eq.) is added to a mixture of potassium carbonate (46.4 mg, 0.34mmol, 3.0 eq.), acetone (1.75 mL) and water (0.35 mL). The mixture isstirred for 10 min at rt, then B-5c (60.0 mg, 0.11 mmol) dissolved inacetone (1.75 mL) and water (0.35 mL) is added and the mixture isstirred for 15 min at rt. After complete conversion, the mixture isconcentrated and the crude product is purified via basic reversed phasechromatography (gradient elution: 10% to 98% acetonitrile in water)yielding Ia-3.

The following compounds (1) according to the invention of sub-genus Ia(table 36) are available in an analogous manner using differentanalogues B-5. The crude product Ia is purified by chromatography ifnecessary.

In some cases the synthesis is carried out using a mixture ofdiastereomers as the starting material and the enantiopure finalcompounds are separated by chiral SFC if necessary.

TABLE 36 IC₅₀ t_(ret) HPLC G12C::SOS1 # structure [min] [M + H]⁺ method[nm] Ia-3

1.31 590 A 1.2 Ia-4

1.42 618 A 1.7 Ia-5

1.42 618 A 622 Ia-6

1.37 617 A 311 Ia-7

1.17 537 A 247 Ia-8

1.43 656 A 1001 Ia-9

1.33 640 A 216 Ia-10

1.41 642 A 254 Ia-11

1.42 642 A 125 Ia-12

1.24 588 A 117 Ia-13

1.23 588 A n.a. Ia-14

1.26 588 A 9 Ia-15

1.29 602 A 53 Ia-16

1.25 600 A 106 Ia-17

0.69 600 B 260 Ia-18

1.14 616 A 364 Ia-19

1.39 660 A 5 Ia-20

1.26 614 A 130 Ia-21

1.29 616 A 51 Ia-22

1.32 628 A 40 Ia-23

1.26 614 A 47 Ia-24

1.30 678 A 406 Ia-25

1.21 600 A 186 Ia-26

1.31 603 A 1.9 Ia-27

1.13 560 A 240 Ia-28

1.17 657 A 152 Ia-29

1.19 644 A 48 Ia-30

1.25 659 A 103 Ia-31

1.32 616 A 83 Ia-32

1.25 643 A 255 Ia-33

1.16 553 A 442 Ia-34

1.44 642 A 259 Ia-35

1.19 644 A 105 Ia-36

1.24 628 A 24 Ia-37

1.28 642 A 47 Ia-38

1.28 646 A 22 Ia-39

1.28 646 A 10 Ia-40

1.28 646 A 19 Ia-41

1.45 673 A 1.8 Ia-42

1.40 661 A 1.8 Ia-43

1.36 659 A 1.7 Ia-44

1.35 659 A 1.5 Ia-45

1.40 675 A 6 Ia-46

1.28 604 A 1.7 Ia-47

1.23 590 A 3 Ia-48

1.29 616 A 8 Ia-49

1.28 630 A 4 Ia-50

1.25 628 A 11 Ia-51

n.a. n.a. — 19 Ia-52

1.23 618 A 1.8 Ia-53

1.33 632 A 1.8 Ia-54

1.31 618 A 1.6 Ia-55

1.32 632 A 2 Ia-56

1.30 632 A 105 Ia-57

1.36 630 A 1.5 Ia-58

1.33 632 A 319 Ia-59

1.31 630 A 3 Ia-60

1.34 644 A 1.7 Ia-61

1.31 618 A 1.6 Ia-62

1.36 632 A 1.6 Ia-63

1.32 618 A 2.6 Ia-64

1.36 632 A 2.2 Ia-65

1.25 616 A 1.6 Ia-66

1.21 633 A 9 Ia-67

1.28 616 A 15 Ia-68

1.21 590 A 27 Ia-69

1.24 616 A 23 Ia-70

1.22 616 A 49 Ia-71

1.27 602 A 3 Ia-72

1.27 616 A 7 Ia-73

1.32 576 A 222 Ia-74

1.35 592 A 61 Ia-75

1.22 576 A 180 Ia-76

1.23 602 A 391 Ia-77

1.35 630 A 2 Ia-78

1.33 657 A 155 Ia-79

1.32 603 A 4 Ia-80

1.32 603 A 507 Ia-81

1.31 604 A 1.6 Ia-82

1.31 604 A 2 Ia-83

1.40 643 A 2 Ia-84

1.41 657 A 3 Ia-85

1.37 604 A 1.6 Ia-86

1.47 646 A 2 Ia-87

1.17 574 A 51 Ia-88

1.24 589 A 71 Ia-89

1.11 563 A 48 Ia-90

1.20 562 A 250 Ia-91

1.24 589 A 49 Ia-92

1.47 701 A 16 Ia-93

1.29 617 A 381 Ia-94

1.31 629 A 77 Ia-95

1.31 629 A 46 Ia-96

1.38 643 A 799 Ia-97

1.28 629 A 43 Ia-98

1.46 715 A 59 Ia-99

1.36 716 A 45 Ia-100

1.35 658 A 84 Ia-101

1.25 615 A 44 Ia-102

1.37 627 A 117 Ia-103

1.35 629 A 143 Ia-104

1.27 602 A 635 Ia-105

1.28 602 A 145 Ia-106

1.35 628 A 180 Ia-107

1.26 602 A 198 Ia-108

1.21 588 A 182 Ia-109

1.16 574 A 943 Ia-110

1.27 602 A 76 Ia-111

1.43 643 A 418 Ia-112

1.20 575 A 73 Ia-113

1.16 610 A 730 Ia-114

1.25 603 A 11 Ia-115

1.29 640 A 63 Ia-116

1.12 574 A 31 Ia-117

1.15 575 A 468 Ia-118

1.24 589 A 21 Ia-119

1.24 588 A 80 Ia-120

1.29 603 A 405 Ia-121

1.29 614 A 50 Ia-122

1.35 628 A 71 Ia-123

1.22 588 A 39 Ia-124

1.16 588 A 158 Ia-125

1.21 606 A 232 Ia-126

1.22 588 A 30 Ia-127

1.24 575 A 60 Ia-128

1.18 577 A 64 Ia-129

1.39 647 A 6 Ia-130

1.33 646 A 7 Ia-131

1.33 603 A 5 Ia-132

1.18 590 A 515 Ia-133

1.29 632 A 12 Ia-134

1.22 590 A 3 Ia-135

1.27 687 A 2 Ia-136

1.32 604 A 1.4 Ia-137

1.41 618 A 1.8 Ia-138

1.34 618 A 2 Ia-139

1.30 605 A 1.5 Ia-140

1.42 618 A 622 Ia-141

1.24 589 A 71 Ia-142

1.33 576 A 176 Ia-143

1.18 600 A 340 Ia-144

1.27 588 A 647 Ia-145

1.27 603 A 377 Ia-146

1.29 614 A 50 Ia-147

1.35 628 A 71 Ia-148

1.24 600 A 24 Ia-149

1.28 614 A 47 Ia-150

1.30 616 A 71 Ia-151

1.33 595 A 1194 Ia-152

1.03 602 A 43 Ia-153

1.24 600 A 31 Ia-154

1.38 660 A n.a.

The compounds Ia depicted in table 37 below are available in ananalogous manner to the conversion of C-5a to Ic-8 described furtherbelow starting from different intermediates B-5 and the correspondingcarboxylic acids. The crude products Ia are purified by chromatographyif necessary.

TABLE 37 IC₅₀ t_(ret) HPLC G12C::SOS1 # structure [min] [M + H]⁺ method[nM] Ia-155

1.32 618 A 10 Ia-156

1.33 618 A 33 Ia-156*

1.26 648 A 5 Ia-157

1.30 648 A 16 Ia-158

1.19 703 A 4 Ia-159

1.36 662 A 5 Ia-160

1.33 674 A 11 Ia-161

1.36 674 A 21 Ia-162

1.40 664 A 252 Ia-163

1.37 644 A 22

The compounds Ia depicted in table 38 below are available in ananalogous manner to the conversion of C-5a to Ic-8 described furtherbelow starting from different intermediates B-5 and 2-butynoic acid. Thecrude products Ia are purified by chromatography if necessary.

TABLE 38 IC₅₀ t_(ret) HPLC G12C::SOS1 # structure [min] [M + H]⁺ method[nM] Ia-164

1.32 618 A 5 Ia-165

1.40 642 A 4 Ia-166

1.37 642 A 3 Ia-167

1.39 656 A 15 Ia-168

1.22 586 A 1022

Experimental Procedure for the Synthesis of Ia-169

B-5f (70.0 mg, 0.13 mmol) in dry DMF (0.75 mL) is treated with TEA (46.0μL, 0.32 mmol, 2.5 eq.) followed by(2E)-4-bromo-N,N-dimethylbut-2-enamide (33.63 mg, 0.14 mmol, 1.1 eq.)dissolved in DMF (0.75 mL). The mixture is stirred for 48 h at rt. Aftercomplete conversion the product is isolated via basic reversed phasechromatography (gradient elution: 15% to 52% acetonitrile in water)yielding Ia-169 (HPLC method A; t_(ret)=1.23 min; [M+H]⁺=661).

TABLE 39 IC₅₀ t_(ret) HPLC G12C::SOS1 # structure [min] [M + H]⁺ method[nM] Ia-169

1.23 661 A 40

Experimental Procedure for the Synthesis of Ia-170

Ia-155 (84 mg, 0.13 mmol, 1 eq.) is dissolved in DCM (1 mL) andtrifluoroacetic acid (145 mg, 1.27 mmol, 10 eq.) is added. The mixtureis stirred at rt for 1 h. The mixture is concentrated in vacuo thenpurified using basic reverse phase chromatography(acetonitrile:water=30:70→90:10). This is followed by purification usingacidic reverse phase (acetonitrile:water=5:95→60:40). Ia-170 is obtainedafter lyophilisation of the product containing fractions.

TABLE 40 IC₅₀ t_(ret) HPLC G12C::SOS1 # structure [min] [M + H]⁺ method[nM] Ia-170

1.14 560 A 87

The following Examples describe the biological activity of the compoundsaccording to the invention, without restricting the invention to theseExamples.

KRAS::SOS1 AlphaScreen Binding Assay

This assay can be used to examine the potency with which compoundsaccording to the invention binding to KRAS G12C inhibit theprotein-protein interaction between SOS1 and KRAS G12C. This inhibitsthe GEF functionality of SOS1 and locks KRAS G12C in its inactive,GDP-bound state. Low IC₅₀ values in this assay setting are indicative ofstrong inhibition of protein-protein interaction between SOS1 and KRAS:

Reagents:

-   -   GST-tagged SOS1 (564_1049_GST_TEV_ECO) produced in-house    -   GST-TEV-SOS1 (564-1049) is purchased from Viva Biotech Ltd.    -   The expression construct of KRAS G12C (amino acids 1-169 of        reference sequence P01116-2 (uniprot), with additional        mutations: C51S, C80L, and C118S) containing a C-terminal        avi-tag was obtained by gene synthesis (GeneArt, Thermo Fisher)        in donor vector (pDONR-221) and transferred by recombinant        cloning into pDEST17 vector bearing an N-terminal His6-tag. The        protein was expressed in E. coli and the purified protein was        biotinylated with the E. coli biotin ligase (BirA) before usage.    -   GDP (Sigma Cat No G7127)    -   AlphaLISA Glutathione Acceptor Beads (PerkinElmer, Cat No AL109)    -   AlphaScreen Streptavidin Donor Beads (PerkinElmer Cat No        6760002)    -   Assay plates: Proxiplate-384 PLUS, white (PerkinElmer, Cat No        6008289)

Assay buffer:

-   -   1×PBS    -   0.1% BSA    -   0.05% Tween 20

KRAS::SOS1 GDP mix:

7.5 nM (final assay concentration) KRAS G12C, 10 μM (final assayconcentration) GDP and 5 nM (final assay concentration) GST-SOS1 aremixed in assay buffer prior to use and kept at room temperature.

Bead Mix:

AlphaLISA Glutathione Acceptor Beads and AlphaScreen Streptavidin DonorBeads are mixed in assay buffer at a concentration of 10 μg/mL (finalassay concentration) each prior to use and kept at room temperature.

Assay Protocol:

Compounds are diluted to a final start concentration of 100 μM and aretested in duplicate. Assay-ready plates (ARPs) are generated using anAccess Labcyte Workstation with a Labcyte Echo 550 or 555 accousticdispenser. For compound a start concentration of 100 μM, 150 nL ofcompound solution is transferred per well in 11 concentrations induplicate with serial 1:5 dilutions.

The assay is run using a fully automated robotic system in a darkenedroom below 100 Lux. 10 μL of KRAS::SOS1 GDP mix is added into columns1-24 to the 150 nL of compound solution (final dilution in the assay1:100, final DMSO concentration 1%).

After 30 minutes incubation time 5 μL of bead mix is added into columns1-23. Plates are kept at room temperature in a darkened incubator. Afterfurther 60 minutes incubation, the signal is measured using aPerkinElmer Envision HTS Multilabel Reader using the AlphaScreenspecifications from PerkinElmer. Each plate contains the followingcontrols:

-   -   diluted DMSO+KRAS::SOS1 GDP mix+bead mix    -   diluted DMSO+KRAS::SOS1 GDP mix

Result Calculation:

IC₅₀ values are calculated and analyzed using a 4 parametric logisticmodel.

Tables of example compounds disclosed herein contain IC₅₀ valuesdetermined using the above assay.

Ba/F3 Cell Model Generation and Proliferation Assay

Ba/F3 cells were ordered from DSMZ (ACC300, Lot17) and grown inRPMI-1640 (ATCC 30-2001)+10% FCS+10 ng/mL IL-3 at 37° C. in 5% CO₂atmosphere. Plasmids containing KRASG12 mutants were obtained fromGeneScript. To generate KRASG12-dependent Ba/F3 models, Ba/F3 cells weretransduced with retroviruses containing vectors that harbor KRASG12isoforms. Platinum-E cells (Cell Biolabs) were used for retroviruspackaging. Retrovirus was added to Ba/F3 cells. To ensure infection, 4μg/mL polybrene was added and cells were spinfected. Infectionefficiency was confirmed by measuring GFP-positive cells using a cellanalyzer. Cells with an infection efficiency of 10% to 20% were furthercultivated and puromycin selection with 1 μg/mL was initiated. As acontrol, parental Ba/F3 cells were used to show selection status.Selection was considered successful when parental Ba/F3 cells culturesdied. To evaluate the transforming potential of KRASG12 mutations, thegrowth medium was no longer supplemented with IL-3. Ba/F3 cellsharboring the empty vector were used as a control. Approximately tendays before conducting the experiments, puromycin was left out.

For proliferation assays, Ba/F3 cells were seeded into 384-well platesat 1×10³ cells/60 μL in growth media (RPMI-1640+10% FCS). Compounds wereadded using an Access Labcyte Workstation with a Labcyte Echo 550 or 555accoustic dispenser. All treatments were performed in technicalduplicates. The assay is run using a fully automated robotic system.Treated cells were incubated for 72 h at 37° C. with 5% CO₂.

AlamarBlue™ (ThermoFisher), a viability stain, was added andfluorescence measured in the PerkinElmer Envision HTS Multilabel Reader.The raw data were imported into and analyzed with the BoehringerIngelheim proprietary software MegaLab (curve fitting based on theprogram PRISM, GraphPad Inc.).

IC₅₀ values of representative compounds (1) according to the inventionmeasured with this assay are presented in table 41.

TABLE 41 IC₅₀ Ba/F3 KRASG12C # [nM] Ia-3 0.3 Ia-4 1.0 Ia-14 51.8 Ia-15219.3 Ia-19 25.6 Ia-26 3.3 Ia-34 4381.0 Ia-39 87.6 Ia-41 10.2 Ia-43 2.7Ia-44 2.5 Ia-46 4.4 Ia-47 185.6 Ia-48 97.6 Ia-49 26.0 Ia-50 495.8 Ia-5218.4 Ia-53 4.3 Ia-54 4.3 Ia-55 24.2 Ia-56 303.2 Ia-57 5.9 Ia-58 3480.9Ia-59 32.5 Ia-60 5.9 Ia-61 2.3 Ia-62 1.2 Ia-63 15.0 Ia-64 12.0 Ia-6518.7 Ia-71 23.7 Ia-72 77.8 Ia-74 254.2 Ia-77 6.9 Ia-78 702.0 Ia-79 7.7Ia-80 559.0 Ia-81 1.9 Ia-82 17.3 Ia-83 7.4 Ia-84 9.9 Ia-85 0.7 Ia-86 7.0Ia-88 381.0 Ia-92 178.5 Ia-94 2286.8 Ia-95 945.7 Ia-97 966.8 Ia-98 661.6Ia-99 1042.9 Ia-100 2197.3 Ia-101 933.4 Ia-114 12.6 Ia-116 207.7 Ia-119396.2 Ia-127 1431.2 Ia-128 681.0 Ia-129 22.5 Ia-130 37.4 Ia-131 22.4Ia-132 1306.6 Ia-133 77.7 Ia-134 15.4 Ia-135 25.4 Ia-136 2.0 Ia-137 0.5Ia-139 2.1 Ia-141 381.0 Ia-155 270.6 Ia-156 2509.1 Ia-156* 140.9 Ia-1571523.3 Ia-158 466.8 Ia-159 16.2 Ia-160 116.0 Ia-161 161.9 Ia-162 3310.4Ia-163 431.4 Ia-164 33.3 Ia-165 12.5 Ia-166 13.4 Ia-167 189.4 Ia-1697734.7

Additional Proliferation Assays with G12C Mutant Cancer Cell Lines

-   -   SW 837 CTG proliferation assay (CRC)

SW837 cells (ATCC #CCL-235) were grown in cell culture flasks (175 cm²)using L-15 10% FCS, 1% L-Glu, 1xNEAA and 1× Na-Pyrovat. Cultures wereincubated at 37° C. and 0% CO₂ in a humidified atmosphere, with mediumchange or subcultivation 2-3 times a week. Materials used for the assaywere CulturPlate-384, White Opaque 384-well Microplate, Sterile andTissue Culture Treated (Perkin Elmer #6007680), Leibovitz L15 Medium andFBS #SH30071.03 (HyClone).

The proliferation assays started (day1) with seeding cells in flatbottom 384 well microtiter plates in 90 μL L-15 10% FCS, 1% L-Glu,1xNEAA and 1×Na-Pyrovat at a density of 500 cells/well. Any otherluminescence compatible plate format is possible. On day 2, 10 μLdilutions of the test compounds covering a concentration range betweenapp. 0,1 and 10.000 nM were added to the cells. Cells were incubated for5 days in a humidified, CO₂ controlled (no CO₂) incubator at 37° C. Onday 7 100 μL of Cell Titer Glow reagent (Cell titer Glo Luminescent Cat.No. G7571, Promega) were added to each well and incubated for additional10 min at room temperature (with agitation). Luminescence was measuredon a Wallac Victor using standard luminescence read out. IC₅₀ valueswere calculated using standard Levenburg Marquard algorithms (GraphPadPrism).

IC₅₀ values of representative compounds (I) according to the inventionmeasured with this assay are presented in table 42.

-   -   MiaPaCa-2 CTG proliferation assay (pancreatic cancer)

MiaPaCa-2 cells (ATCC® CRM-CRL-1420™) were grown in cell culture flasks(175 cm²) using DMEM medium supplemented with 10% fetal bovine serum.Cultures were incubated at 37° C. and 5% CO₂ in a humidified atmosphere,with medium change or subcultivation 2-3 times a week. Materials usedfor the assay were CulturPlate-384, White Opaque 384-well microplate,Sterile and Tissue Culture Treated (Perkin Elmer #6007680), DMEM mediumand FBS #SH30071.03 (HyClone).

The proliferation assays started (day1) with seeding cells in flatbottom 384 well microtiter plates in 90 μL DMEM medium supplemented with10% FBS at a density of 500 cells/well. Any other luminescencecompatible plate format is possible. On day 2, 10 μL dilutions of thetest compounds covering a concentration range between app. 0,1 and10.000 nM were added to the cells. Cells were incubated for 5 days in ahumidified, incubator with 5% CO₂ at 37° C. On day 7 100 μl of CellTiter Glow reagent (Cell titer Glo Luminescent Cat. No. G7571, Promega)were added to each well and incubated for additional 10 min at roomtemperature (with agitation). Luminescence was measured on a WallacVictor using standard luminescence read out. IC₅₀ values were calculatedusing standard Levenburg Marquard algorithms (GraphPad Prism).

IC₅₀ values of representative compounds (1) according to the inventionmeasured with this assay are presented in table 42.

-   -   NCI-H358 CTG proliferation assay (120 h) (NSCLC)

NCI-H358 cells (ATCC No. CRL-5807) were dispensed into white bottomopaque 96 well plates (Perkin Elmer cat no. 5680) at a density of 2000cells per well in 100 μL RPMI-1640 ATCC-Formulation (Gibco #A10491)+10%FCS. Cells were incubated overnight at 37° C. in a humidified tissueculture incubator at 5% CO₂. Compounds (10 mM stock in DMSO) were addedat logarithmic dose series using the HP Digital Dispenser D300 (Tecan),normalizing for added DMSO. For the T0 time point measurement, untreatedcells were analyzed at the time of compound addition. Plates wereincubated for 120 hours, and cell viability was measured usingCellTiter-Glo luminescent cell viability reagent (Promega product codeG7570). Viability (stated as percent of control) is defined as relativeluminescence units RLU of each well divided by the RLU of cells in DMSOcontrols. IC₅₀ values were determined from viability measurements bynon-linear regression using a four parameter model.

IC₅₀ values of representative compounds (I) according to the inventionmeasured with this assay are presented in table 42.

-   -   NCI-H2122 CTG proliferation assay (120 h) (NSCLC)

The CTG assay is designed to measure quantitatively the proliferation ofNCI-H2122 cells (ATCC CRL-5985), using the CellTiter Glow Assay Kit(Promega G7571). Cells are grown in RPMI medium (ATCC) supplemented withFetal Calf Serum (Life Technologies, Gibco BRL, Cat. No. 10270-106). On“day 0” 1000 NCI-H2122 cells are seeded in 60 μL RPMI ATCC+10%FCS+Penstrep in a 384-well plate, flat bottom. Cells are then incubatedin the plates at 37° C. in a CO₂ incubator overnight. On day 1,compounds are added with the ECHO acoustic liquid handler system(Beckman Coulter), including DMSO controls. Plates were incubated for120 hours, and cell viability was measured using CellTiter-Gloluminescent cell viability reagent (Promega product code G7570).Viability (stated as percent of control) is defined as relativeluminescence units RLU of each well divided by the RLU of cells in DMSOcontrols. IC₅₀ values were determined from viability measurements bynon-linear regression using a four parameter model.

TABLE 42 IC₅₀ IC₅₀ IC₅₀ SW837 MiaPACA2 NCI-H358 # [nM] [nM] [nM] Ia-46<1 3.0 0.95 Ia-54 2.25 2.22 1.34 Ia-61 0.63 4.23 0.67 Ia-62 0.42 6.771.01 Ia-64 6.34 12.08 7.42 Ia-77 4.11 13.34 4.20 Ia-86 2.08 13.84 4.67Ia-133 71.0 673.0 41.38 sotorasib 17.0 49.0 21.0 adagrasib 13.0 28.010.0

ERK Phosphorylation Assay

ERK phosphorylation assays are used to examine the potency with whichcompounds inhibit the KRAS G12C-mediated signal transduction in a KRASG12C mutant human cancer cell line in vitro. This demonstrates themolecular mode of action of compounds according to the invention byinterfering with the RAS G12C protein signal transduction cascade. LowIC₅₀ values in this assay setting are indicative of high potency of thecompounds according to the invention. It is observed that compoundsaccording to the invention demonstrate an inhibitory effect on ERKphosphorylation in a KRAS G12C mutant human cancer cell line, thusconfirming the molecular mode of action of the compounds on RAS G12Cprotein signal transduction.

ERK phosphorylation assays are performed using the following human celllines: NCI-H358 (ATCC (ATCC CRL-5807): human lung cancer with a KRASG12C mutation (→ assay 1) and NCI-H358_Cas9_SOS2, i.e. the same cellline, in which SOS2 was knocked (→ assay 2). Vectors containing thedesigned DNA sequences for the production of gRNA for SOS2 proteinknock-out were obtained from Sigma-Aldrich. To generate the NCI-H358SOS2 knock-out cell line, NCI-H358 cells expressing Cas9 endonucleasewere transfected with XtremeGene9 reagent and the correspondentplasmids. Transfection efficiency was confirmed by measuringGFP-positive cells using a cell analyzer. GFP positive cells werecollected and further expanded. These GFP-positive cell pools weresingle-cell diluted and SOS2 knock-out clones were identified viaWestern-blot and genomic DNA sequencing analysis.

Materials Used for the Assay:

RPMI-1640 Medium (ATCC® 30-2001™)

Fetal Bovine Serum (FBS) from HyClone (SH30071.03)

Non-essential amino acids from Thermo Fischer Scientific (11140035)

Pyruvate from Thermo Fischer Scientific (11360039)

Glutamax from Thermo Fischer Scientific (35050061)

384 plates from Greiner Bio-One (781182)

Proxiplate™ 384 from PerkinElmer Inc. (6008280)

AlphaLISA SureFire Ultra p-ERK1/2 (Thr202/Tyr204) Assay Kit(ALSU-PERK-A500)

EGF from Sigma (E4127)

Acceptor Mix: Protein A Acceptor Beads from PerkinElmer (6760137M)

Donor Mix: AlphaScreen Streptavidin-coated Donor Beads from PerkinElmer(6760002)

Trametinib

Staurosporine from Sigma Aldrich (S6942)

Assay Setup:

Cells are seeded at 40,000 cells per well in /60 μL of RPMI with 10%FBS, non-essential amino acids, pyruvate and glutamax in Greiner TC 384plates. The cells are incubated for 1 h at room temperature and thenincubated overnight in an incubator at 37° C. and 5% CO₂ in a humidifiedatmosphere. 60 nL compound solution (10 mM DMSO stock solution) is thenadded using a Labcyte Echo 550 device. After a 1 h incubation in theaforementioned incubator the medium is removed after centrifugation andthe cells lysed by addition of 20 μL of 1.6-fold lysis buffer from theAlphaLISA SureFire Ultra pERK1/2 (Thr202/Tyr204) Assay Kit with addedprotease inhibitors, 100 nM trametinib+100 nM staurosporine. After 20minutes of incubation at room temperature with shaking, 6 μL of eachlysate sample is transferred to a 384-well Proxiplate and analyzed forpERK (Thr202/Tyr204) with the AlphaLISA SureFire Ultra pERK1/2(Thr202/Tyr204) Assay Kit. 3 μL Acceptor Mix and 3 μL Donor Mix areadded under subdued light and incubated for 2 h at room temperature inthe dark, before the signal is measured on a PerkinElmer Envision HTSMultilabel Reader. The raw data were imported into and analyzed with theBoehringer Ingelheim proprietary software MegaLab (curve fitting basedon the program PRISM, GraphPad Inc.).

IC₅₀ values of representative compounds (I) according to the inventionmeasured with this assay are presented in table 57 (IC₅₀s from assay 2are marked with *, all others are from assay 1).

TABLE 42 IC₅₀ H358 # pERK [nM] Ia-1 31.4 Ia-2 130.6 Ia-3 0.5* Ia-4 1.1*Ia-6 206.1* Ia-7 30.3 Ia-8 544.0 Ia-9 54.6 Ia-10 38.5 Ia-11 12.3 Ia-1213.5 Ia-13 7.3 Ia-14 2.7 Ia-15 7.3 Ia-16 24.6 Ia-17 29.4 Ia-18 57.4Ia-19 6.2 Ia-20 20.7 Ia-21 7.4 Ia-22 6.7 Ia-23 6.5 Ia-24 80.1 Ia-25112.4 Ia-26 1.5* Ia-27 61.6 Ia-28 784.6 Ia-29 7.8 Ia-30 20.1 Ia-32 35.6Ia-33 50.4 Ia-34 281.6 Ia-35 12.4 Ia-36 12.2 Ia-37 12.3 Ia-38 5.8 Ia-396.2 Ia-40 5.3 Ia-42 2.8 Ia-46 2.1* Ia-48 21.3* Ia-49 10.4* Ia-50 121.2*Ia-51 98.5* Ia-53 3.1* Ia-54 2.2* Ia-55 9.8* Ia-56 62.1* Ia-57 0.9*Ia-58 299.8* Ia-59 5.5* Ia-60 2.8* Ia-61 1.3* Ia-62 1.2* Ia-63 10.9*Ia-64 3.5* Ia-65 60.5* Ia-66 123.8* Ia-67 176.8* Ia-68 268.7* Ia-69298.2* Ia-70 413.1* Ia-71 21.4* Ia-72 50.9* Ia-73 138.5* Ia-75 552.6*Ia-76 1001.0* Ia-77 2.6* Ia-78 458.5* Ia-79 18.7* Ia-80 1148.5* Ia-811.7* Ia-82 7.7* Ia-83 10.2* Ia-84 11.0* Ia-85 0.7* Ia-86 3.9* Ia-87 10.0Ia-88 39.6 Ia-91 11.6 Ia-104 71.8 Ia-105 14.4 Ia-106 25.2 Ia-107 29.3Ia-108 19.8 Ia-109 5990.5 Ia-110 8.7 Ia-111 92.5 Ia-112 18.5 Ia-113376.4 Ia-114 4.1 Ia-115 8.8 Ia-116 6.4 Ia-117 120.4 Ia-118 7.5 Ia-11924.2 Ia-120 111.3 Ia-121 9.9 Ia-122 19.3 Ia-123 9.5 Ia-124 76.6 Ia-125233.4 Ia-126 4.2 Ia-127 22.1 Ia-128 13.3 Ia-129 6.4 Ia-130 16.6 Ia-1316.2 Ia-132 1352.9* Ia-133 28.9* Ia-134 5.6* Ia-135 9.6* Ia-136 0.9*Ia-137 0.7* Ia-138 7.8* Ia-139 1.4* Ia-141 39.6 Ia-142 36.4 Ia-1431328.7 Ia-144 68.7 Ia-145 93.5 Ia-146 9.9 Ia-147 19.3 Ia-148 5.9 Ia-1498.6 Ia-150 9.5 Ia-151 182.5 Ia-152 5.9 Ia-153 11.6 Ia-155 39.8* Ia-156190.8* Ia-156* 35.9* Ia-157 238.2* Ia-158 102.9* Ia-159 12.4* Ia-16025.3* Ia-161 26.5* Ia-162 1973.3* Ia-163 81.3* Ia-164 8.0* Ia-165 4.0*Ia-166 4.2* Ia-167 77.2* Ia-169 1842.7* Ia-170 269.1

The formulation examples which follow illustrate the present inventionwithout restricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance according to formula (I) 100 mglactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesiumstearate 5 mg 500 mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B) Tablets per tablet active substance according to formula (I) ) 80 mglactose 55 mg corn starch 190 mg microcrystalline cellulose 35 mgpolyvinylpyrrolidone 15 mg sodiumcarboxymethyl starch 23 mg magnesiumstearate 2 mg 400 mg

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. Thesodiumcarboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize.

C) Tablets per tablet active substance according to formula (I) 25 mglactose 50 mg microcrystalline cellulose 24 mg magnesium stearate 1 mg100 mg

The active substance, lactose and cellulose are mixed together. Themixture is screened, then either moistened with water, kneaded,wet-granulated and dried or dry-granulated or directly final blend withthe magnesium stearate and compressed to tablets of suitable shape andsize. When wet-granulated, additional lactose or cellulose and magnesiumstearate is added and the mixture is compressed to produce tablets ofsuitable shape and size.

D) Ampoule solution active substance according to formulae (I) 50 mgsodium chloride 50 mg water for inj. 5 mL

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50mg of active substance.

1. A compound of the formula (I)

wherein R^(1a) and R^(1b) are both independently selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy,C₁₋₄haloalkoxy, halogen, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,C₃₋₅cycloalkyl and 3-5 membered heterocyclyl; R^(2a) and R^(2b) are bothindependently selected from the group consisting of hydrogen, C₁₋₄alkyl,C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄haloalkoxy, halogen, —NH₂,—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, C₃₋₅cycloalkyl and 3-5 memberedheterocyclyl; and/or, optionally, one of R^(1a) or R^(1b) and one ofR^(2a) or R^(2b) together with the carbon atoms they are attached form acyclopropane ring; Z is —(CR^(6a)R^(6b))_(n)—; each R^(6a) and R^(6b) isindependently selected from the group consisting of hydrogen, C₁₋₄alkyl,C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄haloalkoxy, halogen, —NH₂,—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, C₃₋₅cycloalkyl and 3-5 memberedheterocyclyl; n is selected from the group consisting 0, 1 and 2; R³ isselected from the group consisting of hydrogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, cyano-C₁₋₆alkyl, halogen,—OH, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —CN, C₃₋₅cycloalkyl and 3-5membered heterocyclyl; ring A is an oxadiazole or a thiadiazole; U isselected from the group consisting of nitrogen (═N—) and carbonsubstituted with R^(A)(═C(R^(A))—); V is selected from the groupconsisting of nitrogen (═N—) and carbon substituted with R^(B)(═C(R^(B))—); W is selected from the group consisting of nitrogen (═N—)and carbon substituted with R^(C) (═C(R^(C))—); R^(A), R^(B) and R^(C)is each independently selected from the group consisting of hydrogen,C₁₋₆haloalkyl, C₂₋₆alkynyl optionally substituted with C₃₋₅cycloalkyl,C₁₋₆alkoxy, C₁₋₆haloalkoxy, halogen, —CN, —OH, —NH₂, —NH(C₁₋₄alkyl),—N(C₁₋₄alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl), —C(═O)N(C₁₋₄alkyl)₂,—S—C₁₋₆alkyl, —S(═O)₂—C₁₋₆alkyl, C₃₋₅cycloalkyl, 3-5 memberedheterocyclyl and C₁₋₆alkyl optionally substituted with a substituentselected from the group consisting of C₁₋₆alkoxy, —CN, —OH, —NH₂,—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl) and—C(═O)N(C₁₋₄alkyl)₂; R⁵ is selected from the group consisting of R^(a1)and R^(b1); R^(a1) is selected from the group consisting of C₁₋₆alkyl,C₁₋₆haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl,C₄₋₁₀cycloalkenyl, 3-11 membered heterocyclyl, C₆₋₁₀aryl and 5-10membered heteroaryl, wherein the C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, 3-11 memberedheterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are all optionallysubstituted with one or more, identical or different R^(b1) and/orR^(c1); each R^(b1) is independently selected from the group consistingof —OR^(c1), —NR^(c1)R^(c1), halogen, —CN, —C(═O)R^(c1), —C(═O)OR^(c1),—C(═O)NR^(c1)R^(c1), —S(═O)₂R^(c1), —S(═O)₂NR^(c1)R^(c1),—NHC(═O)R^(c1), —N(C₁₋₄alkyl)C(═O)R^(c1), —NHS(═O)₂R^(c1),—N(C₁₋₄alkyl)S(═O)₂R^(c1), —NHC(═O)OR^(c1), —N(C₁₋₄alkyl)C(═O)OR^(c1)and the bivalent substituent ═O; each R^(c1) is independently selectedfrom the group consisting of hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, 3-11membered heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl, whereinthe C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl,C₄₋₁₀cycloalkenyl, 3-11 membered heterocyclyl, C₆₋₁₀aryl and 5-10membered heteroaryl are all optionally substituted with one or more,identical or different R^(d1) and/or R^(e1); each R^(d1) isindependently selected from the group consisting of —OR^(e1),—NR^(e1)R^(e1), halogen, —CN, —C(═O)R^(e1), —C(═O)OR^(e1),—C(═O)NR^(e1)R^(e1), —S(═O)₂R^(e1), —S(═O)₂NR^(e1)R^(e1),—NHC(═O)R^(e1), —N(C₁₋₄alkyl)C(═O)R^(e1), —NHS(═O)₂R^(c1),—N(C₁₋₄alkyl)S(═O)₂R^(c1), —NHC(═O)OR^(e1), —N(C₁₋₄alkyl)C(═O)OR^(e1)and the bivalent substituent ═O; each R^(e1) is independently selectedfrom the group consisting of hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, 3-11membered heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl, whereinthe C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl,C₄₋₁₀cycloalkenyl, 3-11 membered heterocyclyl, C₆₋₁₀aryl and 5-10membered heteroaryl are all optionally substituted with one or more,identical or different substituent(s) selected from the group consistingof C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11 membered heterocyclyloptionally substituted with one or more, identical or differentC₁₋₄alkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, —OH, C₁₋₆alkoxy,C₁₋₄alkoxy-C₁₋₄alkyl, hydroxy-C₁₋₄alkyl, halogen, —CN, —NH₂,—C(═O)C₁₋₄alkyl, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂ and the bivalentsubstituent ═O; L is -L¹-L²-L³-, wherein L¹ is linked to E; L¹ isselected from the group consisting of a bond, —NH—, —N(C₁₋₄alkyl)-, —O—,—C(═O)—, —NH—C(═O)—, —N(C₁₋₄alkyl)-C(═O)—, —C(═O)—NH—,—C(═O)—N(C₁₋₄alkyl)-, —C(═O)—, C₁₋₆alkylen, C₃₋₇cycloalkylene,phenylene, 4-12 membered heterocyclylene and 5-10 memberedheteroarylene; L² is selected from the group consisting of C₁₋₆alkylen,C₃₋₇cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10membered heteroarylene; L³ is selected from the group consisting of abond, —NH—, —N(C₁₋₄alkyl)-, —O—, —C(═O)—, —NH—C(═O)—,—N(C₁₋₄alkyl)-C(═O)—, —C(═O)—NH—, —C(═O)—N(C₁₋₄alkyl)-, —C(═O)—,C₁₋₆alkylen, C₃₋₇cycloalkylene, phenylene, 4-12 membered heterocyclyleneand 5-10 membered heteroarylene; wherein each C₁₋₆alkylen,C₃₋₇cycloalkylene, phenylene, 4-12 membered heterocyclylene and 5-10membered heteroarylene in L¹, L² and L³ is optionally and independentlysubstituted with one or more, identical or different substituent(s)selected from the group consisting of C₂₋₆alkinyl, C₁₋₆haloalkyl,C₃₋₇cycloalkyl, phenyl, 5-6 membered heteroaryl, halogen, —OH, —CN,C₁₋₆alkoxy, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —C(═O)OH,—C(═O)—OC₁₋₆alkyl, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl), —C(═O)N(C₁₋₄alkyl)₂,the bivalent substituent ═O and C₁₋₆alkyl optionally substituted withone or more, identical or different substituent(s) selected from thegroup consisting of halogen, —OH, —CN, C₁₋₄alkoxy, —NH₂, —NH(C₁₋₄alkyl),—N(C₁₋₄alkyl)₂, —C(═O)OH, —C(═O)—OC₁₋₆alkyl, —C(═O)NH₂,—C(═O)NH(C₁₋₄alkyl) and —C(═O)N(C₁₋₄alkyl)₂; E is

represents a double or a triple bond; Q¹ is selected from the groupconsisting of a bond, —CH₂—, —CH(OH)—, —C(═O)—, —C(═O)N(R^(G1)),—C(═O)O—, —S(═O)₂—, —S(═O)₂N(R^(G1))— and —C(═NR^(H1))—; each R^(G1) isindependently selected from the group consisting of hydrogen, C₁₋₆alkyl,C₁₋₆haloalkyl, hydroxy-C₁₋₆alkyl, H₂N—C₁₋₆alkyl, cyano-C₁₋₆alkyl,(C₁₋₄alkyl)HN—C₁₋₆alkyl, (C₁₋₄alkyl)₂N—C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl,C₃₋₇cycloalkyl and 3-11 membered heterocyclyl; each R^(H1) isindependently selected from the group consisting of hydrogen, —OH,C₁₋₆alkoxy, —CN and C₁₋₆alkyl; if

represents a double bond then R^(D) is selected from the groupconsisting of hydrogen, C₃₋₇cycloalkyl, phenyl, halogen, —CN,C₁₋₆alkoxy, —C(═O)O—C₁₋₆alkyl, —NHC(═O)—C₁₋₆alkyl and C₁₋₆alkyloptionally substituted with one or more, identical or differentsubstituent(s) selected from the group consisting of phenyl, 3-11membered heterocyclyl, C₁₋₆alkoxy, halogen, —OH, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C(═O)OH, —C(═O)O—C₁₋₆alkyl, —C(═O)NH(C₁₋₆alkyl),—NHC(═O)—C₁₋₆alkyl, —OC(═O)—C₁₋₆alkyl and phenyl-C₁₋₆alkoxy; R^(E) andR^(F) is each independently selected from the group consisting of R^(a2)and R^(b2); R^(a2) is selected from the group consisting of hydrogen,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11 membered heterocyclyl,C₆₋₁₀aryl and 5-10 membered heteroaryl, wherein the C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11 membered heterocyclyl, C₆₋₁₀aryland 5-10 membered heteroaryl are all optionally substituted with one ormore, identical or different R^(b2) and/or R^(c2); each R^(b2) isindependently selected from the group consisting of —OR^(c2),—NR^(c2)R^(c2), halogen, —CN, —C(═O)R^(c2), —C(═O)OR^(c2),—C(═O)NR^(c2)R^(c2), —S(═O)₂R^(c2), —S(═O)₂NR^(c2)R^(c2),—NHC(═O)R^(c2), —N(C₁₋₄alkyl)C(═O)R^(c2), —NHC(═O)OR^(c2),—N(C₁₋₄alkyl)C(═O)OR^(c2) and the bivalent substituent ═O; each R^(c2)is independently selected from the group consisting of hydrogen,C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl,C₄₋₁₀cycloalkenyl, 3-11 membered heterocyclyl, C₆₋₁₀aryl and 5-10membered heteroaryl, wherein the C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, C₄₋₁₀cycloalkenyl, 3-11 memberedheterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are all optionallysubstituted with one or more, identical or different substituent(s)selected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen,—OH, —C(═O)OH, —C(═O)O—C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, —C(═O)NH₂,—C(═O)NH(C₁₋₆alkyl), —C(═O)N(C₁₋₆alkyl)₂, and the bivalent substituent═O; or R^(D) and R^(E) taken together with the carbon atoms they areattached form a 4-7 membered unsaturated alicycle or 4-7 memberedunsaturated heterocycle, wherein this 4-7 membered unsaturated alicycleor 4-7 membered unsaturated heterocycle is optionally, in addition toR^(F), substituted with one or more identical or differentsubstituent(s) selected from the group consisting of C₁₋₆alkyl,C₁₋₆haloalkyl, —OH, C₁₋₆alkoxy, C₁₋₄alkoxy-C₁₋₄alkyl, —NH₂, —CN,—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, halogen, —C(═O)O—C₁₋₆alkyl and thebivalent substituent ═O; or if Q¹ is —C(═O)N(R^(G1))—, then R^(G1) of—C(═O)N(R^(G1))— and R^(F) together form a linker selected from thegroup consisting of —C(═O)—, —CH₂—, —CH₂—C(═O)—, —C(═O)—CH₂— and —C₂H₄—;if

represents a triple bond then R^(D) and R^(E) are both absent; R^(F) isR^(a2); R^(a2) is selected from the group consisting of hydrogen,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11 membered heterocyclyl,C₆₋₁₀aryl and 5-10 membered heteroaryl, wherein the C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11 membered heterocyclyl, C₆₋₁₀aryland 5-10 membered heteroaryl are all optionally substituted with one ormore, identical or different R^(b2) and/or R^(c2); each R^(b2) isindependently selected from the group consisting of —OR^(c2),—NR^(c2)R^(c2), halogen, —CN, —C(═O)R^(c2), —C(═O)OR^(c2),—C(═O)NR^(c2)R^(c2), —S(═O)₂R^(c2), —S(═O)₂NR^(c2)R^(c2),—NHC(═O)R^(c2), —N(C₁₋₄alkyl)C(═O)R^(c2), —NHC(═O)OR^(c2),—N(C₁₋₄alkyl)C(═O)OR^(c2) and the bivalent substituent ═O; each R^(c2)is independently selected from the group consisting of hydrogen,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11 membered heterocyclyl,C₆₋₁₀aryl and 5-10 membered heteroaryl; or E is

Q² is selected from the group consisting of a bond, —CH₂—, —CH(OH)—,—C(═O)—, —C(═O)N(R^(G2))—, —C(═O)O—, —S(═O)₂—, —S(═O)₂N(R^(G2))— and—C(═NR^(H2))—; each R^(G2) is independently selected from the groupconsisting of hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, hydroxy-C₁₋₆alkyl,H₂N—C₁₋₆alkyl, cyano-C₁₋₆alkyl, (C₁₋₄alkyl)HN—C₁₋₆alkyl,(C₁₋₄alkyl)₂N—C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl, C₃₋₇cycloalkyl and 3-11membered heterocyclyl; each R^(H2) is independently selected from thegroup consisting of hydrogen, —OH, C₁₋₆alkoxy, —CN and C₁₋₆alkyl; R^(I)is selected from the group consisting of hydrogen and halogen; R^(J) ishydrogen; or R^(I) and R^(J) together with the carbon atoms they areattached form a cyclopropane or oxirane ring; R^(K) is selected from thegroup consisting of hydrogen, C₁₋₆alkyl, —CN and halogen; R^(L) isselected from the group consisting of hydrogen, C₁₋₆alkyl, —CN, halogenand —C(═O)—C₁₋₆alkyl; or E is

Q³ is selected from the group consisting of —C(═O)—, —C(═O)N(R^(G3))—,—C(═O)O—, —S(═O)₂—, —S(═O)₂N(R^(G3))— and —C(═NR^(H3))—; each R^(G3) isindependently selected from the group consisting of hydrogen, C₁₋₆alkyl,C₁₋₆haloalkyl, hydroxy-C₁₋₆alkyl, H₂N—C₁₋₆alkyl, cyano-C₁₋₆alkyl,(C₁₋₄alkyl)HN—C₁₋₆alkyl, (C₁₋₄alkyl)₂N—C₁₋₆alkyl, C₁₋₆alkoxy-C₁₋₆alkyl,C₃₋₇cycloalkyl and 3-11 membered heterocyclyl; each R^(H3) isindependently selected from the group consisting of hydrogen, —OH,C₁₋₆alkoxy, —CN and C₁₋₆alkyl; R^(M) is selected from the groupconsisting of halogen, —CN and —O—C(═O)—C₁₋₆alkyl; or E is

Q⁴ is selected from the group consisting of a bond, —C(═O)—, —C(═O)O—,—C(═O)NH—, —C(═O)N(C₁₋₄alkyl)-, —S(═O)₂— and —S(═O)₂NH—; ring B isselected from the group consisting of phenyl, pyridyl, pyrimidyl,pyridazinyl, pyrazinyl and 5-membered heteroaryl; q is selected from thegroup consisting 1, 2, 3 and 4; each R^(N) is independently selectedfrom the group consisting of C₁₋₄alkyl, C₁₋₄haloalkyl, vinyl, ethinyl,halogen, —CN, nitro and C₁₋₄alkoxy; or a salt thereof.
 2. The compoundor salt according to claim 1 of the formula (Ia)

wherein R^(1a), R^(1b), R^(2a), R^(2b), Z, R³, U, V, W, R⁵, L and E aredefined as in in claim
 1. 3. A compound of the formula (II)

wherein R^(1a), R^(1b), R^(2a), R^(2b), Z, R³, ring A, U, V, W, R⁵ and Lare defined as in formula (I) in claim 1, or a salt thereof.
 4. Thecompound or salt according to claim 1, wherein R^(1a) and R^(1b) areboth independently selected from the group consisting of hydrogen andC₁₋₄alkyl; R^(2a) and R^(2b) are both independently selected from thegroup consisting of hydrogen and halogen.
 5. The compound or saltaccording to claim 1, wherein R³ is selected from the group consistingof hydrogen, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, C₁₋₄haloalkoxy,cyano-C₁₋₄alkyl, halogen, —OH, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂ and—CN.
 6. The compound or salt according to claim 1, wherein ring A isselected from the group consisting of


7. The compound or salt according to claim 1, wherein U is carbonsubstituted with R^(A) (═C(R^(A))—); V is carbon substituted with R^(B)(═C(R^(B))—); W is nitrogen (═N—); R^(A) and R^(B) is each independentlyselected from the group consisting of hydrogen, C₁₋₆haloalkyl,C₂₋₆alkynyl optionally substituted with C₃₋₅cycloalkyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, halogen, —CN, —OH, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,—C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl), —C(═O)N(C₁₋₄alkyl)₂, C₃₋₅cycloalkyl, 3-5membered heterocyclyl and C₁₋₆alkyl optionally substituted with asubstituent selected from the group consisting of C₁₋₆alkoxy, —CN, —OH,—NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl) and—C(═O)N(C₁₋₄alkyl)₂.
 8. The compound or salt according to claim 1,wherein U is carbon substituted with R^(A) (═C(R^(A))—); V is carbonsubstituted with R^(B) (═C(R^(B))—); W is carbon substituted with R^(C)(═C(R^(C))—); R^(A), R^(B) and R^(C) is each independently selected fromthe group consisting of hydrogen, C₁₋₆haloalkyl, C₂₋₆alkynyl optionallysubstituted with C₃₋₅cycloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, halogen,—CN, —OH, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —C(═O)NH₂,—C(═O)NH(C₁₋₄alkyl), —C(═O)N(C₁₋₄alkyl)₂, C₃₋₅cycloalkyl, 3-5 memberedheterocyclyl and C₁₋₆alkyl optionally substituted with a substituentselected from the group consisting of C₁₋₆alkoxy, —CN, —OH, —NH₂,—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl) and—C(═O)N(C₁₋₄alkyl)₂.
 9. The compound or salt according to claim 1,wherein U is nitrogen (═N—); V is carbon substituted with R^(B)(═C(R^(B))—); W is nitrogen (═N—); R^(B) is selected from the groupconsisting of hydrogen, C₁₋₆haloalkyl, C₂₋₆alkynyl optionallysubstituted with C₃₋₅cycloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, halogen,—CN, —OH, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —C(═O)NH₂,—C(═O)NH(C₁₋₄alkyl), —C(═O)N(C₁₋₄alkyl)₂, C₃₋₅cycloalkyl, 3-5 memberedheterocyclyl and C₁₋₆alkyl optionally substituted with a substituentselected from the group consisting of C₁₋₆alkoxy, —CN, —OH, —NH₂,—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl) and—C(═O)N(C₁₋₄alkyl)₂.
 10. The compound or salt according to claim 1,wherein U is carbon substituted with R^(A) (═C(R^(A))—); V is nitrogen(═N—); W is nitrogen (═N—); R^(A) is selected from the group consistingof hydrogen, C₁₋₆haloalkyl, C₂₋₆alkynyl optionally substituted withC₃₋₅cycloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, halogen, —CN, —OH, —NH₂,—NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl),—C(═O)N(C₁₋₄alkyl)₂, C₃₋₅cycloalkyl, 3-5 membered heterocyclyl andC₁₋₆alkyl optionally substituted with a substituent selected from thegroup consisting of C₁₋₆alkoxy, —CN, —OH, —NH₂, —NH(C₁₋₄alkyl),—N(C₁₋₄alkyl)₂, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl) and —C(═O)N(C₁₋₄alkyl)₂.11. The compound or salt according to claim 1, wherein U is nitrogen(═N—); V is nitrogen (═N—); W is nitrogen (═N—).
 12. The compound orsalt according to claim 1, wherein R⁵ is selected from the groupconsisting of R^(a1) and R^(b1); R^(a1) is selected from the groupconsisting of C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl,3-11 membered heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl,wherein the C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkynyl, C₃₋₁₀cycloalkyl, 3-11membered heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are alloptionally substituted with one or more, identical or different R^(b1)and/or R^(c1); each R^(b1) is independently selected from the groupconsisting of —OR^(c1), —NR^(c1)R^(c1), halogen, —CN, —C(═O)R^(c1),—C(═O)OR^(c1), —C(═O)NR^(c1)R^(c1), —S(═O)₂R^(c1), —S(═O)₂NR^(c1)R^(c1),—NHC(═O)R^(c1), —N(C₁₋₄alkyl)C(═O)R^(c1) and the bivalent substituent═O; each R^(c1) is independently selected from the group consisting ofhydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11 memberedheterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl, wherein theC₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11 membered heterocyclyl,C₆₋₁₀aryl and 5-10 membered heteroaryl are all optionally substitutedwith one or more, identical or different R^(d1) and/or R^(e1); eachR^(d1) is independently selected from the group consisting of —OR^(e1),—NR^(e1)R^(e1), halogen, —CN, —C(═O)R^(e1), —C(═O)NR^(e1)R^(e1) and thebivalent substituent ═O; each R^(e1) is independently selected from thegroup consisting of hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,3-11 membered heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl,wherein the C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11 memberedheterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are all optionallysubstituted with one or more, identical or different substituent(s)selected from the group consisting of C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl, 3-11 membered heterocyclyl optionally substituted withone or more, identical or different C₁₋₄alkyl, C₆₋₁₀aryl, 5-10 memberedheteroaryl, —OH, C₁₋₆alkoxy, C₁₋₄alkoxy-C₁₋₄alkyl, hydroxy-C₁₋₄alkyl,halogen, —CN, —NH₂, —C(═O)C₁₋₄alkyl, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂ andthe bivalent substituent ═O.
 13. The compound or salt according to claim1, wherein R⁵ is R^(a1); R^(a1) is selected from the group consisting of3-11 membered heterocyclyl and 5-10 membered heteroaryl, wherein the3-11 membered heterocyclyl and 5-10 membered heteroaryl are alloptionally substituted with one or more, identical or different R^(b1)and/or R^(c1); each R^(b1) is independently selected from the groupconsisting of —OR^(c1), —NR^(c1)R^(c1), halogen, —C(═O)OR^(c1) and thebivalent substituent ═O; each R¹ is independently selected from thegroup consisting of hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyland 3-11 membered heterocyclyl, wherein the C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₁₀cycloalkyl and 3-11 membered heterocyclyl are all optionallysubstituted with one or more, identical or different R^(d1) and/orR^(e1); each R^(d1) is independently selected from the group consistingof —OR^(e1), —NR^(e1)R^(e1) and halogen; each R^(e1) is independentlyselected from the group consisting of hydrogen, C₁₋₆alkyl,C₃₋₁₀cycloalkyl and 3-11 membered heterocyclyl, wherein the C₁₋₆alkyl,C₃₋₁₀cycloalkyl and 3-11 membered heterocyclyl are all optionallysubstituted with one or more, identical or different substituent(s)selected from the group consisting of C₁₋₆alkyl and 3-11 memberedheterocyclyl optionally substituted with one or more, identical ordifferent C₁₋₄alkyl.
 14. The compound or salt according to claim 1,wherein R⁵ is R^(b1); R^(b1) is independently selected from the groupconsisting of —OR^(c1) and —NR^(c1)R^(c1); each R^(c1) is independentlyselected from the group consisting of hydrogen, C₁₋₆alkyl,C₃₋₁₀cycloalkyl, 3-11 membered heterocyclyl, C₆₋₁₀aryl and 5-10 memberedheteroaryl, wherein the C₁₋₆alkyl, C₃₋₁₀cycloalkyl, 3-11 memberedheterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are all optionallysubstituted with one or more, identical or different R^(d1) and/orR^(e1); each R^(d1) is independently selected from the group consistingof —OR^(e1), —NR^(e1)R^(e1), halogen, —C(═O)R^(e1) and—C(═O)NR^(e1)R^(e1); each R^(e1) is independently selected from thegroup consisting of hydrogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl, 3-11 memberedheterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl, wherein theC₁₋₆alkyl, C₃₋₁₀cycloalkyl, 3-11 membered heterocyclyl, C₆₋₁₀aryl and5-10 membered heteroaryl are all optionally substituted with one ormore, identical or different substituent(s) selected from the groupconsisting of C₁₋₆alkyl, C₁₋₆haloalkyl, 3-11 membered heterocyclyloptionally substituted with one or more, identical or differentC₁₋₄alkyl, C₁₋₆alkoxy, halogen and the bivalent substituent ═O.
 15. Thecompound or salt according to claim 1, wherein L is -L¹-L²-L³-, whereinL¹ is linked to E; L¹ is selected from the group consisting of a bond,C₁₋₆alkylen and 4-12 membered heterocyclylene; L² is selected from thegroup consisting of C₁₋₆alkylen, phenylene and 4-12 memberedheterocyclylene; L³ is selected from the group consisting of a bond,—NH—, —N(C₁₋₄alkyl)- and —O—; wherein each C₁₋₆alkylen, phenylene and4-12 membered heterocyclylene in L¹ and L² is optionally andindependently substituted with one or more, identical or differentsubstituent(s) selected from the group consisting of C₂₋₆alkinyl,C₁₋₆haloalkyl, C₃₋₇cycloalkyl, phenyl, 5-6 membered heteroaryl, halogen,—OH, —CN, C₁₋₆alkoxy, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂, —C(═O)OH,—C(═O)—OC₁₋₆alkyl, —C(═O)NH₂, —C(═O)NH(C₁₋₄alkyl), —C(═O)N(C₁₋₄alkyl)₂,the bivalent substituent ═O and C₁₋₆alkyl optionally substituted withone or more, identical or different substituent(s) selected from thegroup consisting of halogen, —OH, —CN, —NH₂, C₁₋₄alkoxy, —NH(C₁₋₄alkyl),—N(C₁₋₄alkyl)₂, —C(═O)OH, —C(═O)—OC₁₋₆alkyl, —C(═O)NH₂,—C(═O)NH(C₁₋₄alkyl) and —C(═O)N(C₁₋₄alkyl)₂.
 16. The compound or saltaccording to claim 15, wherein L is selected from the group consistingof


17. The compound or salt according to claim 1, wherein E is

Q¹ is selected from the group consisting of —CH₂—, —C(═O)—,—C(═O)N(R^(G1))—, —C(═O)O—, —S(═O)₂—, —S(═O)₂N(R^(G1))— and—C(═NR^(H1))—; each R^(G1) is independently selected from the groupconsisting of hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl and hydroxy-C₁₋₆alkyl;each R^(H1) is independently selected from the group consisting ofhydrogen, —OH, C₁₋₆alkoxy, —CN and C₁₋₆alkyl; R^(D) is selected from thegroup consisting of hydrogen, C₃₋₇cycloalkyl, phenyl, halogen, —CN,C₁₋₆alkoxy, —C(═O)O—C₁₋₆alkyl and C₁₋₆alkyl optionally substituted withone or more, identical or different substituent(s) selected from thegroup consisting of phenyl, 3-11 membered heterocyclyl, C₁₋₆alkoxy,halogen, —OH, —N(C₁₋₆alkyl)₂, —C(═O)OH, —C(═O)O—C₁₋₆alkyl,—C(═O)NH(C₁₋₆alkyl), —NHC(═O)—C₁₋₆alkyl, —OC(═O)—C₁₋₆alkyl andphenyl-C₁₋₆alkoxy; R^(E) and R^(F) is each independently selected fromthe group consisting of R^(a2) and R^(b2); R^(a2) is selected from thegroup consisting of hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl,3-11 membered heterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl,wherein the C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₁₀cycloalkyl, 3-11 memberedheterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are all optionallysubstituted with one or more, identical or different R^(b2) and/orR^(c2); each R^(b2) is independently selected from the group consistingof —OR^(c2), —NR^(c2)R^(c2), halogen, —CN, —C(═O)OR^(c2),—C(═O)NR^(c2)R^(c2), —NHC(═O)R^(c2), —N(C₁₋₄alkyl)C(═O)R^(c2),—NHC(═O)OR^(c2) and —N(C₁₋₄alkyl)C(═O)OR^(c2); each R^(c2) isindependently selected from the group consisting of hydrogen, C₁₋₆alkyl,C₁₋₆haloalkyl, 3-11 membered heterocyclyl, C₆₋₁₀aryl and 5-10 memberedheteroaryl, wherein the C₁₋₆alkyl, C₁₋₆haloalkyl, 3-11 memberedheterocyclyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are all optionallysubstituted with one or more, identical or different substituent(s)selected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, halogen,—OH, —C(═O)OH, —C(═O)O—C₁₋₆alkyl, —C(═O)C₁₋₆alkyl, —C(═O)NH₂,—C(═O)NH(C₁₋₆alkyl), —C(═O)N(C₁₋₆alkyl)₂, and the bivalent substituent═O.
 18. The compound or salt according to claim 17, wherein E isselected from the group consisting of


19. The compound or salt according to claim 1, wherein E is

Q¹ is selected from the group consisting of —CH₂—, —C(═O)—, —C(═O)N(RG),—C(═O)O—, —S(═O)₂—, —S(═O)₂N(R^(G1))— and —C(═NR^(H1))—; each R^(G1) isindependently selected from the group consisting of hydrogen, C₁₋₆alkyl,C₁₋₆haloalkyl and hydroxy-C₁₋₆alkyl; each R^(H1) is independentlyselected from the group consisting of hydrogen, —OH, C₁₋₆alkoxy, —CN andC₁₋₆alkyl; R^(F) is selected from the group consisting of hydrogen andC₁₋₆alkyl optionally substituted with a substituent selected from thegroup consisting of —OH, C₁₋₆alkoxy, —NH₂, —NH(C₁₋₄alkyl) and—N(C₁₋₄alkyl)₂.
 20. The compound or salt according to claim 19, whereinE is selected from the group consisting of


21. (canceled)
 22. A method for the treatment and/or prevention ofcancer in a patient, comprising administering to said patient atherapeutically effective amount of a compound of formula (I) accordingto claim 1, or a Pharmaceutically acceptable salt thereof.
 23. Themethod according to claim 22, wherein said compound or salt isadministered before, after or together with one or more otherpharmacologically active substance(s).
 24. The method according to claim22, wherein said compound or salt is administered in combination withone or more other pharmacologically active substance(s).
 25. The methodaccording to claim 22, wherein the cancer is selected from the groupconsisting of pancreatic cancer, lung cancer, colorectal cancer,cholangiocarcinoma, appendiceal cancer, multiple myeloma, melanoma,uterine cancer, endometrial cancer, thyroid cancer, acute myeloidleukaemia, bladder cancer, urothelial cancer, gastric cancer, cervicalcancer, head and neck squamous cell carcinoma, diffuse large B celllymphoma, oesophageal cancer, chronic lymphocytic leukaemia,hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer,glioblastoma, renal cancer and sarcoma.
 26. A pharmaceutical compositioncomprising a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptableexcipient(s).
 27. A pharmaceutical composition comprising a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, andone or more other pharmacologically active substance(s).